[Oculo-facio-cardio-dental syndrome caused by BCOR gene mutations: a case report]. / BCORåŸºå› çªå˜è‡´æ–°ç”Ÿå„¿çœ¼-面-心-牙综合征1例.

A full-term female infant was admitted at 5 hours after birth due to heart malformations found during the fetal period and cyanosis once after birth. Mmultiple malformations of eyes, face, limbs, and heart were noted. The whole-exome sequencing revealed a pathogenic heterozygous mutation, c.2428C>T(p.Arg810*), in the BCOR gene. The infant was then diagnosed with oculo-facio-cardio-dental syndrome. He received assisted ventilation to improve oxygenation and nutritional support during hospitalization. Right ventricular double outlet correction was performed 1 month after birth. Ocular lesions were followed up and scheduled for elective surgery. The possibility of oculo-facio-cardio-dental syndrome should be considered for neonates with multiple malformations of eyes, face, and heart, and genetic testing should be performed as early as possible to confirm the diagnosis; meanwhile, active ophthalmic and cardiovascular symptomatic treatment should be given to improve the prognosis.

A Patient with Kabuki Syndrome Mutation Presenting with Very Severe Aplastic Anemia.

Kabuki syndrome (KS) is a rare congenital disorder commonly complicated by humoral immunodeficiency. Patients with KS present with mutation in the histone-lysine N-methyltransferase 2D (KMT2D) gene. Although various KMT2D mutations are often identified in lymphoma and leukemia, those encountered in aplastic anemia (AA) are limited. Herein, we present the case of a 45-year-old Japanese man who developed severe pancytopenia and hypogammaglobulinemia. He did not present with any evident malformations, intellectual disability, or detectable levels of autoantibodies. However, B-cell development was impaired. Therefore, a diagnosis of very severe AA due to a hypoplastic marrow, which did not respond to granulocyte colony-stimulating factor, was made. The patient received umbilical cord blood transplantation but died from a Pseudomonas infection before neutrophil engraftment. Trio whole-exome sequencing revealed a novel missense heterozygous mutation c.15959G >A (p.R5320H) in exon 50 of the KMT2D gene. Moreover, Sanger sequencing of peripheral blood and bone marrow mononuclear cells and a skin biopsy specimen obtained from this patient identified this heterozygous mutation, suggesting that de novo mutation associated with KS occurred in the early embryonic development. Our case showed a novel association between KS mutation and adult-onset AA.

Cornelia de Lange syndrome: from molecular diagnosis to therapeutic approach.

Cornelia de Lange syndrome (CdLS) is a severe genetic disorder characterised by multisystemic malformations. CdLS is due to pathogenetic variants in NIPBL, SMC1A, SMC3, RAD21 and HDAC8 genes which belong to the cohesin pathway. Cohesin plays a pivotal role in chromatid cohesion, gene expression, and DNA repair. In this review, we will discuss how perturbations in those biological processes contribute to CdLS phenotype and will emphasise the state-of-art of CdLS therapeutic approaches.

22q11.2 deletion syndrome: 20 years of experience from two pediatric immunology units and review of clues for diagnosis and disease management.

INTRODUCTION AND OBJECTIVES: The purpose of this study was to evaluate patients diagnosed with 22q11.2 deletion syndrome and determine the clues directing to diagnosis and evaluation of immunological findings for excellent management of the disease. MATERIAL AND METHODS: Thirty-three pediatric patients with 22q11.2 deletion syndrome diagnosed between 1998 and 2019 at Pediatric Immunology Division of Ege University Faculty of Medicine and SBU Izmir Dr Behcet Uz Children's Education and Research Hospital were evaluated. RESULTS: This study includes the largest case series reported from Turkey. Congenital cardiac anomalies were the most common pathology associated with the syndrome (90.9%). Hypocalcemic symptoms were observed in 13 patients (40%). Twenty-two of the 33 (66.6%) patients were diagnosed before two years of age. Autoimmune diseases, dysmorphic facial findings, recurrent infections, growth retardation, and speech impairment were other clues for diagnosis in older patients. Clinical spectrum and immunological abnormalities of this syndrome are quite variable. All T-cell subset counts were less than 5th percentile below median by age in one patient (3%) and 10 patients had normal all T-cell subset counts (30.3%). Overall, 69.6% of the patients had normal IgG, IgA, and IgM levels and two patients had panhypogammaglobulinemia. Recurrent infections were revealed in 75.7% of the patients during follow-up. CONCLUSIONS: Presence of cardiac anomaly is more helpful in the diagnosis, especially under two years of age. Patients with immunologically high or standard risk did not show any difference in terms of numbers and severity of infections and autoimmunity.

An antibody to Notch3 reverses the skeletal phenotype of lateral meningocele syndrome in male mice.

Lateral meningocele syndrome (LMS), a genetic disorder characterized by meningoceles and skeletal abnormalities, is associated with NOTCH3 mutations. We created a mouse model of LMS (Notch3tm1.1Ecan ) by introducing a tandem termination codon in the Notch3 locus upstream of the proline (P), glutamic acid (E), serine (S) and threonine (T) domain. Microcomputed tomography demonstrated that Notch3tm1.1Ecan mice exhibit osteopenia. The cancellous bone osteopenia was no longer observed after the intraperitoneal administration of antibodies directed to the negative regulatory region (NRR) of Notch3. The anti-Notch3 NRR antibody suppressed the expression of Hes1, Hey1, and Hey2 (Notch target genes), and decreased Tnfsf11 (receptor activator of NF Kappa B ligand) messenger RNA in Notch3tm1.1Ecan osteoblast (OB) cultures. Bone marrow-derived macrophages (BMMs) from Notch3tm1.1Ecan mutants exhibited enhanced osteoclastogenesis in culture, and this was increased in cocultures with Notch3tm1.1Ecan OB. Osteoclastogenesis was suppressed by anti-Notch3 NRR antibodies in Notch3tm1.1Ecan OB/BMM cocultures. In conclusion, the cancellous bone osteopenia of Notch3tm1.1Ecan mutants is reversed by anti-Notch3 NRR antibodies.

Congenital heart defects in Noonan syndrome: Diagnosis, management, and treatment.

Noonan syndrome is a pleomorphic genetic disorder, in which a high percentage of affected individuals have cardiovascular involvement, most prevalently various forms of congenital heart disease (i.e., pulmonary valve stenosis, septal defects, left-sided lesions, and complex forms with multiple anomalies). Care includes attentiveness to several comorbidities, some directly impacting cardiac management (bleeding diatheses and lymphatic anomalies). More than 50% of patients with Noonan syndrome harbor PTPN11 pathogenic variation, which results in hyperactivation of RAS/mitogen-activated protein kinase signaling. Several other disease genes with similar biological effects have been uncovered for NS and phenotypically related disorders, collectively called the RASopathies. Molecular diagnosis with gene resequencing panels is now widely available, but phenotype variability and in some cases, subtlety, continues to make identification of Noonan syndrome difficult. Until genetic testing becomes universal for patients with congenital heart disease, alertness to Noonan syndrome's broad clinical presentations remains crucial. Genotype-phenotype associations for Noonan syndrome enable better prognostication for affected patients when a molecular diagnosis is established. We still lack Noonan syndrome-specific treatment; however, newly developed anticancer RAS pathway inhibitors could fill that gap if safety and efficacy can be established for indications such as pulmonary valve stenosis.

Healthcare recommendations for Joubert syndrome.

Joubert syndrome (JS) is a recessive neurodevelopmental disorder defined by a characteristic cerebellar and brainstem malformation recognizable on axial brain magnetic resonance imaging as the "Molar Tooth Sign". Although defined by the neurological features, JS is associated with clinical features affecting many other organ systems, particularly progressive involvement of the retina, kidney, and liver. JS is a rare condition; therefore, many affected individuals may not have easy access to subspecialty providers familiar with JS (e.g., geneticists, neurologists, developmental pediatricians, ophthalmologists, nephrologists, hepatologists, psychiatrists, therapists, and educators). Expert recommendations can enable practitioners of all types to provide quality care to individuals with JS and know when to refer for subspecialty care. This need will only increase as precision treatments targeting specific genetic causes of JS emerge. The goal of these recommendations is to provide a resource for general practitioners, subspecialists, and families to maximize the health of individuals with JS throughout the lifespan.

Embolization of congenital portosystemic shunt presenting after pediatric liver transplantation: Case report and literature review.

This case report describes a 13-year 10-month-old girl who underwent a deceased-donor split LT for primary diagnosis of biliary atresia at the age of 12 months, who presented with a lower GI bleed. Ultrasound and CT revealed a venous vascular anomaly involving the cecum and ascending colon, with communication of the SMV and pelvic veins consistent with a CEPS. Associated varices were noted in the pelvis along the uterus and urinary bladder. These findings were confirmed by trans-hepatic porto-venography, which was diagnostic and therapeutic as a successful embolization of the CEPS was performed using micro-coils. There were no complications following the procedure and no further GI bleeding occurred, illustrating the efficacy of this treatment option for CEPS. We discuss the literature regarding the presenting complaint of GI bleeding post-LT, CEPS as a rare cause of GI bleeding and its association with PV, and the classification and treatment of CEPS.

Light and Laser Treatments for Keratosis Pilaris: A Systematic Review.

BACKGROUND: Keratosis pilaris (KP) is a common hereditary keratinization disorder. Keratosis pilaris rubra and KP atrophicans faciei are less frequent variants of the disease. Topical treatments often yield ineffective and temporary results. OBJECTIVE: The objective of this article is to review and assess all the studies that used light and laser devices to treat KP and its variants. MATERIAL AND METHODS: On January 15, 2017, an online search of the MEDLINE, Embase, and Cochrane databases was performed using the following combination of keywords: "keratosis pilaris" and "treatment." RESULTS: Seventeen studies related to light and laser treatments were retained for analysis. The total number of treated patients was 175. Of which, 22 patients had KP atrophicans faciei, 17 patients had KP rubra, and 136 patients had KP. CONCLUSION: Light and laser devices have been emerging as promising therapeutic options for a disfiguring disease that still lacks, until today, an effective long-term treatment.

Health characteristics and health care trajectory of polyhandicaped person before and after 1990.

INTRODUCTION: Polyhandicap is defined as the combination of severe mental impairment and severe motor deficit resulting in reduced mobility and an extreme reduction in autonomy. Over the last 20years, care management for these patients has become more structured, however, their care pathway is not always optimal. OBJECTIVE: To describe/compare the health characteristics, treatment and history of the care pathways of subjects who received care before and after 1990. METHOD: Multicentre cross-sectional study, population studied: patients with polyhandicap: (i) causal brain damage<3years, (ii) severe mental impairment, (iii) motor disability, (iv) reduced mobility, (v) extreme restriction of autonomy. DATA COLLECTED: clinical and medical, care procedures, treatments, history of care pathways. RESULTS: Patients are divided into 2 groups: 545 patients who received care after 1990 and 330 before 1990. Older patients present more recurrent urinary infections, slow transit, behavioural disorders and pain, and are prescribed a greater number of drugs. For those who received care before 1990, the age of admission to an establishment is lower, with one-third receiving a consultation dedicated to the transition from paediatric to adult teams. DISCUSSION/CONCLUSION: The care sector for patients with polyhandicap makes it possible to meet their needs throughout their lives, however, there is still progress to be made in terms of formalisation and of coordinating the care pathway in order to facilitate the transition from paediatric to adult services/establishments.

Congenital anomalies and comorbidities in neonates with Down Syndrome. / Anomalías congénitas y comorbilidad en neonatos con Síndrome de Down.

INTRODUCTION: In Chile, Down syndrome has a prevalence of 2.5 in 1,000 live births. These patients present more congenital anomalies and comorbidities than the general population, increasing their hospitaliza tion rate. OBJECTIVE: To describe congenital anomalies and comorbidities of neonates with Down syndrome born and/or hospitalized between 2008 and 2018. PATIENTS AND METHOD: We conducted a retrospective review of patient's medical records born and/or hospitalized during their first 28 days of life between January 1st, 2008, and December 31st, 2018. For each patient, we recorded maternal age, familiar cases of Down Syndrome, pre and perinatal history, genetic study result, as well as age at admission, reason for hospitalization, comorbidities, length of stay, and death. Two patients that had more than 50% of incomplete medical records were excluded. We studied the associations between comorbidities, congenital anomalies, and death. RESULTS: 140 in 79,506 newborns (0.2%) were diagnosed at our center with Down Syndrome in their neonatal period. 24.7% were born preterm and 26.4% had low birth weight for gestational age. Morbidities and hospitalizations were present in 83.6% and 90%, of the study population, respectively. The main reason for hospitalization was polycythemia and the most frequent was hyperbilirubinemia. Four patients died (2.9%) and 70.7% presented at least one congenital anomaly, mainly heart disease. Median maternal age was 36 years and 57.1% of mothers were aged 35 or older. CONCLUSIONS: This cohort of patients with Down Syndrome provides important information for the optimization of their perinatal management and follow-up.

Prenatal microRNA miR-200b Therapy Improves Nitrofen-induced Pulmonary Hypoplasia Associated With Congenital Diaphragmatic Hernia.

OBJECTIVE: We aimed to evaluate the use of miR-200b as a prenatal transplacental therapy in the nitrofen rat model of abnormal lung development and congenital diaphragmatic hernia (CDH). BACKGROUND: Pulmonary hypoplasia (PH) and pulmonary hypertension determine mortality and morbidity in CDH babies. There is no safe medical prenatal treatment available. We previously discovered that higher miR-200b is associated with better survival in CDH babies. Here, we investigate the role of miR-200b in the nitrofen rat model of PH and CDH and evaluate its use as an in vivo prenatal therapy. METHODS: We profiled miR-200b expression during nitrofen-induced PH using RT-qPCR and in situ hybridization in the nitrofen rat model of PH and CDH. The effects of nitrofen on downstream miR-200b targets were studied in bronchial lung epithelial cells using a SMAD luciferase assay, Western blotting and Immunohistochemistry. We evaluated miR-200b as a lung growth promoting therapy ex vivo and in vivo using lung explant culture and transplacental prenatal therapy in the nitrofen rat model. RESULTS: We show that late lung hypoplasia in CDH is associated with (compensatory) upregulation of miR-200b in less hypoplastic lungs. Increasing miR-200b abundance with mimics early after nitrofen treatment decreases SMAD-driven TGF-ß signaling and rescues lung hypoplasia both in vitro and in vivo. Also, prenatal miR-200b therapy decreases the observed incidence of CDH. CONCLUSIONS: Our data indicate that miR-200b improves PH and decreases the incidence of CDH. Future studies will further exploit this newly discovered prenatal therapy for lung hypoplasia and CDH.

CHRNG-related nonlethal multiple pterygium syndrome: Muscle imaging pattern and clinical, histopathological, and molecular genetic findings.

Mutations in the CHRNG gene cause autosomal recessive multiple pterygium syndrome (MPS). Herein we present a long-term follow-up of seven patients with CHRNG-related nonlethal MPS and we compare them with the 57 previously published patients. The objective is defining not only the clinical, histopathological, and molecular genetic characteristics, but also the type and degree of muscle involvement on whole-body magnetic resonance imaging (WBMRI). CHRNG mutations lead to a distinctive phenotype characterized by multiple congenital contractures, pterygium, and facial dysmorphism, with a stable clinical course over the years. Postnatal abnormalities at the neuromuscular junction were observed in the muscle biopsy of these patients. WBMRI showed distinctive features different from other arthrogryposis multiple congenita. A marked muscle bulk reduction is the predominant finding, mostly affecting the spinal erector muscles and gluteus maximus. Fatty infiltration was only observed in deep paravertebral muscles and distal lower limbs. Mutations in CHRNG are mainly located at the extracellular domain of the protein. Our study contributes to further define the phenotypic spectrum of CHRNG-related nonlethal MPS, including muscle imaging features, which may be useful in distinguishing it from other diffuse arthrogryposis entities.

Prenatal evaluation of the Sakoda complex.

Sakoda complex is a rare but distinct combination of birth defects consisting of a basal cephalocele, agenesis of the corpus callosum, and midline cleft lip/palate. It has been reported in association with ophthalmologic abnormalities, cognitive deficits and severe epilepsy. Here we describe both prenatal and postnatal MRI findings of a classic case of Sakoda complex in a child with characteristic findings on fetal MRI; prenatal findings have not been described in the literature. Diagnosis of this entity has important implications for prenatal counseling and perinatal management, as is demonstrated in this case.

Endoplasmic reticulum stress response is activated in pulmonary hypoplasia secondary to congenital diaphragmatic hernia, but is decreased by administration of amniotic fluid stem cells.

PURPOSE: Pulmonary hypoplasia secondary to congenital diaphragmatic hernia (CDH) is characterized by impaired epithelial homeostasis. Recently, amniotic fluid stem cells (AFSCs) have been shown to promote growth in hypoplastic lungs of rat fetuses with CDH. Herein, we investigated whether CDH hypoplastic lungs mount an endoplasmic reticulum (ER) stress response and whether AFSCs could re-establish pulmonary epithelial homeostasis. METHODS: Primary epithelial cells were isolated from fetal rat lungs at E14.5 from control and nitrofen-exposed dams at E9.5. Nitrofen-exposed epithelial cells were grown in medium alone or co-cultured with AFSCs. Epithelial cell cultures were compared for apoptosis (TUNEL), cytotoxicity (LIVE/DEAD assay), proliferation (5'EdU), and ER stress (CHOP, Bcl-2) using one-way ANOVA (Dunn's post-test). RESULTS: Compared to control, nitrofen-exposed epithelial cells had increased cytotoxicity and apoptosis, reduced proliferation, and activated ER stress. AFSCs restored apoptosis, proliferation, and ER stress back to control levels, and significantly reduced cytotoxicity. CONCLUSIONS: This study shows for the first time that ER stress-induced apoptosis is activated in the pulmonary epithelium of hypoplastic lungs from fetuses with CDH. AFSC treatment restores epithelial cellular homeostasis by attenuating the ER stress response and apoptosis, by increasing proliferation and migration ability, and by reducing cytotoxicity.

Papillon-Léage and psaume syndrome patient with multiple dental and orofacial anomalies.

Papillon-Léage-Psaume Syndrome, also known as oral-facial-digital syndrome (OFDS) type I, describes a group of neurodevelopmental disorders that are characterized by anomalies of the oral cavity, facial features, and the digits. Central nervous system (CNS) anomalies and visceral organ abnormalities such as kidney, pancreas, and ovarian cysts can also be seen in these patients. Among 13 potential types, female-inherited OFDS type I is the most common and it has been reported to be lethal in males. After the identification of the genetic relation of OFDS in 2001, it is now known that, except X-linked OFDS Type I and VIII, generally all types of OFDSs are autosomal recessive. The dentist's knowledge about the syndrome can reduce the development of physical and dental anomalies by facilitating early diagnosis. This article presents a patient with Papillon-Léage-Psaume Syndrome (Oral-Facial-Digital Syndrome Type I).

Nablus syndrome: Easy to diagnose yet difficult to solve.

Nablus syndrome was first described by the late Ahmad Teebi in 2000, and 13 individuals have been reported to date. Nablus syndrome can be clinically diagnosed based on striking facial features, including tight glistening skin with reduced facial expression, blepharophimosis, telecanthus, bulky nasal tip, abnormal external ear architecture, upswept frontal hairline, and sparse eyebrows. However, the precise genetic etiology for this rare condition remains elusive. Comparative microarray analyses of individuals with Nablus syndrome (including two mother-son pairs) reveal an overlapping 8q22.1 microdeletion, with a minimal critical region of 1.84 Mb (94.43-96.27 Mb). Whereas this deletion is present in all affected individuals, 13 individuals without Nablus syndrome (including two mother-child pairs) also have the 8q22.1 microdeletion that partially or fully overlaps the minimal critical region. Thus, the 8q22.1 microdeletion is necessary but not sufficient to cause the clinical features characteristic of Nablus syndrome. We discuss possible explanations for Nablus syndrome, including one-locus, two-locus, epigenetic, and environmental mechanisms. We performed exome sequencing for five individuals with Nablus syndrome. Although we failed to identify any deleterious rare coding variants in the critical region that were shared between individuals, we did identify one common SNP in an intronic region that was shared. Clearly, unraveling the genetic mechanism(s) of Nablus syndrome will require additional investigation, including genomic and RNA sequencing of a larger cohort of affected individuals. If successful, it will provide important insights into fundamental concepts such as variable expressivity, incomplete penetrance, and complex disease relevant to both Mendelian and non-Mendelian disorders.

First data from a parent-reported registry of 81 individuals with Coffin-Siris syndrome: Natural history and management recommendations.

Coffin-Siris syndrome (CSS; MIM 135900) is a multisystem congenital anomaly syndrome caused by mutations in the genes in the Brg-1 associated factors (BAF) complex. Classically, individuals with CSS have been described with hypo- or aplasia of the fifth digit nails or phalanges (hence the term "fifth digit syndrome"). Other physical features seen include growth restriction, coarse facial features, hypertrichosis or hirsutism, sparse scalp hair, dental anomalies, and other organ-system abnormalities. Varying degrees of developmental and intellectual delay are universal. To date, approximately 200 individuals have been described in the literature. With the advent of large-scale genetic testing such as whole-exome sequencing is becoming more available, more individuals are being found to have mutations in this pathway, and the phenotypic spectrum appears to be broadening. We report here a large cohort of 81 individuals with the diagnosis of CSS from the first parent-reported CSS/BAF complex registry in an effort to describe this variation among individuals, the natural history of the syndrome, and draw some gene-phenotype correlations. We propose that changes in the BAF complex may represent a spectrum of disorders, including both ARID1B-related nonsyndromic intellectual disability (ARID1B-ID) and CSS with classic physical features. In addition, we offer surveillance and management recommendations based on the medical issues encountered in this cohort to help guide physicians and patients' families.

CHILD syndrome: A modified pathogenesis-targeted therapeutic approach.

Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects (CHILD syndrome) is a rare X-linked dominant genodermatosis caused by mutations in the NAD(P) dependent steroid dehydrogenase-like protein gene. Its defect leads to accumulation of toxic metabolic intermediates upstream from the pathway block and to the deficiency of bulk cholesterol, probably leading to altered keratinocyte membrane function, resulting in the phenotype seen in CHILD syndrome. Symptomatic treatment using emollients and retinoids to reduce scaling has long been used until recently, whereby new therapeutic means based on the pathogenesis-targeted therapy have been developed. We subsequently chose to use the same pathogenesis-based therapy using a 2% cholesterol and 2% lovastatin cream with or without glycolic acid in two of our patients. Improvement in CHILD skin lesions was seen as early as 4 weeks after initiation. The addition of glycolic acid helped improve the penetrance of the cholesterol and lovastatin cream into the thick waxy scales. Our study confirms the efficacy of the pathogenesis-targeted therapy and introduces the possibility of modifying its formula by adding glycolic acid in order to improve the treatment.