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1.
Am J Hum Genet ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31587868

RESUMO

NKAP is a ubiquitously expressed nucleoplasmic protein that is currently known as a transcriptional regulatory molecule via its interaction with HDAC3 and spliceosomal proteins. Here, we report a disorder of transcriptional regulation due to missense mutations in the X chromosome gene, NKAP. These mutations are clustered in the C-terminal region of NKAP where NKAP interacts with HDAC3 and post-catalytic spliceosomal complex proteins. Consistent with a role for the C-terminal region of NKAP in embryogenesis, nkap mutant zebrafish with a C-terminally truncated NKAP demonstrate severe developmental defects. The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis. In affected cases, transcriptome analysis revealed the presence of a unique transcriptome signature, which is characterized by the downregulation of long genes with higher exon numbers. These observations indicate the critical role of NKAP in transcriptional regulation and demonstrate that perturbations of the C-terminal region lead to developmental defects in both humans and zebrafish.

2.
Genet Med ; 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31474763

RESUMO

PURPOSE: The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion in humans, with highly variable phenotypic expression. Whereas congenital heart defects, palatal anomalies, immunodeficiency, hypoparathyroidism, and neuropsychiatric conditions are observed in over 50% of patients with 22q11DS, a subset of patients present with additional "atypical" findings such as craniosynostosis and anorectal malformations. Recently, pathogenic variants in the CDC45 (Cell Division Cycle protein 45) gene, located within the LCR22A-LCR22B region of chromosome 22q11.2, were noted to be involved in the pathogenesis of craniosynostosis. METHODS: We performed next-generation sequencing on DNA from 15 patients with 22q11.2DS and atypical phenotypic features such as craniosynostosis, short stature, skeletal differences, and anorectal malformations. RESULTS: We identified four novel rare nonsynonymous variants in CDC45 in 5/15 patients with 22q11.2DS and craniosynostosis and/or other atypical findings. CONCLUSION: This study supports CDC45 as a causative gene in craniosynostosis, as well as a number of other anomalies. We suggest that this association results in a condition independent of Meier-Gorlin syndrome, perhaps representing a novel condition and/or a cause of features associated with Baller-Gerold syndrome. In addition, this work confirms that the phenotypic variability observed in a subset of patients with 22q11.2DS is due to pathogenic variants on the nondeleted chromosome.

4.
Genet Med ; 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31388190

RESUMO

PURPOSE: Sifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants in CHD4. In this study, we investigated the clinical spectrum of the disorder, genotype-phenotype correlations, and the effect of different missense variants on CHD4 function. METHODS: We collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains. RESULTS: The majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype-phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains. CONCLUSION: The CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans.

5.
Am J Med Genet A ; 179(10): 2144-2151, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31287223

RESUMO

Warsaw breakage syndrome (WABS), caused by bi-allelic variants in the DDX11 gene, is a rare cohesinopathy characterized by pre- and postnatal growth retardation, microcephaly, intellectual disability, facial dysmorphia, and sensorineural hearing loss due to cochlear hypoplasia. The DDX11 gene codes for an iron-sulfur DNA helicase in the Superfamily 2 helicases and plays an important role in genomic stability and maintenance. Fourteen individuals with WABS have been previously reported in the medical literature. Affected individuals have been of various ethnic backgrounds with different pathogenic variants. We report two unrelated individuals of Ashkenazi Jewish descent affected with WABS, who are homozygous for the c.1763-1G>C variant in the DDX11 gene. Their phenotype is consistent with previously reported individuals. RNA studies showed that this variant causes an alternative splice acceptor site leading to a frameshift in the open reading frame. Carrier screening of the c.1763-1G>C variant in the Jewish population revealed a high carrier frequency of 1 in 68 in the Ashkenazi Jewish population. Due to the high carrier frequency and the low number of affected individuals, we hypothesize a high rate of miscarriage of homozygous fetuses and/or subfertility for carrier couples. If the carrier frequency is reproducible in additional Ashkenazi Jewish populations, we suggest including DDX11 to Ashkenazi Jewish carrier screening panels.

6.
Am J Med Genet A ; 179(10): 2075-2082, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31361404

RESUMO

Zinc finger protein 462 (ZNF462) is a relatively newly discovered vertebrate specific protein with known critical roles in embryonic development in animal models. Two case reports and a case series study have described the phenotype of 10 individuals with ZNF462 loss of function variants. Herein, we present 14 new individuals with loss of function variants to the previous studies to delineate the syndrome of loss of function in ZNF462. Collectively, these 24 individuals present with recurring phenotypes that define a multiple congenital anomaly syndrome. Most have some form of developmental delay (79%) and a minority has autism spectrum disorder (33%). Characteristic facial features include ptosis (83%), down slanting palpebral fissures (58%), exaggerated Cupid's bow/wide philtrum (54%), and arched eyebrows (50%). Metopic ridging or craniosynostosis was found in a third of study participants and feeding problems in half. Other phenotype characteristics include dysgenesis of the corpus callosum in 25% of individuals, hypotonia in half, and structural heart defects in 21%. Using facial analysis technology, a computer algorithm applying deep learning was able to accurately differentiate individuals with ZNF462 loss of function variants from individuals with Noonan syndrome and healthy controls. In summary, we describe a multiple congenital anomaly syndrome associated with haploinsufficiency of ZNF462 that has distinct clinical characteristics and facial features.

7.
Birth Defects Res ; 111(13): 888-905, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31222980

RESUMO

Over 50% of patients with 22q11.2 deletion syndrome (DS) have a conotruncal or related cardiac defect (CTRD). We hypothesized that similar genetic variants, developmental pathways and biological functions, contribute to disease risk for CTRD in patients without a 22q11.2 deletion (ND-CTRD) and with a 22q11.2 deletion (DS-CTRD). To test this hypothesis, we performed rare CNV (rCNV)-based analyses on 630 ND-CTRD cases and 602 DS-CTRD cases with comparable cardiac lesions separately and jointly. First, we detected a collection of heart development related pathways from Gene Ontology and Mammalian Phenotype Ontology analysis. We then constructed gene regulation networks using unique genes collected from the rCNVs found in the ND-CTRD and DS-CTRD cohorts. These gene networks were clustered and their predicted functions were examined. We further investigated expression patterns of those unique genes using publicly available mouse embryo microarray expression data from single-cell embryos to fully developed hearts. By these bioinformatics approaches, we identified a commonly shared gene expression pattern in both the ND-CTRD and DS-CTRD cohorts. Computational analysis of gene functions characterized with this expression pattern revealed a collection of significantly enriched terms related to cardiovascular development. By our combined analysis of rCNVs in the ND-CTRD and DS-CTRD cohorts, a group of statistically significant shared pathways, biological functions, and gene expression patterns were identified that can be tested in future studies for their biological relevance.

9.
Am J Med Genet A ; 179(8): 1442-1450, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31111620

RESUMO

Muenke syndrome (MIM #602849), the most common syndromic craniosynostosis, results from the recurrent pathogenic p.P250R variant in FGFR3. Affected patients exhibit wide phenotypic variability. Common features include coronal craniosynostosis, hearing loss, carpal and tarsal anomalies, and developmental/behavioral issues. Our study examined the phenotypic findings, medical management, and surgical outcomes in a cohort of 26 probands with Muenke syndrome identified at the Children's Hospital of Philadelphia. All probands had craniosynostosis; 69.7% had bicoronal synostosis only, or bicoronal and additional suture synostosis. Three male patients had autism spectrum disorder. Recurrent ear infections were the most common comorbidity, and myringotomy tube placement the most common extracranial surgical procedure. Most patients (76%) required only one fronto-orbital advancement. de novo mutations were confirmed in 33% of the families in which proband and both parents were genetically tested, while in the remaining 66% one of the parents was a mutation carrier. In affected parents, 40% had craniosynostosis, including 71% of mothers and 13% of fathers. We additionally analyzed the medical resource utilization of probands with Muenke syndrome. To our knowledge, these data represent the first comprehensive examination of long-term management in a large cohort of patients with Muenke syndrome. Our study adds valuable information regarding neuropsychiatric and medical comorbidities, and highlights findings in affected relatives.

10.
Am J Med Genet A ; 179(6): 1063-1068, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30924273

RESUMO

We evaluated a newborn with acrofacial dysostosis in whom a clinical diagnosis of Nager syndrome was entertained. Radiographs revealed hypoplasia of the scapulae and bilateral humeroradial synostosis, with absent ulna on the left and hypoplastic ulna on the right. The finding of bilateral humeroradial synostosis had not been seen in cases of Nager syndrome before and we considered other diagnoses. Humeroradial synostosis has been found in three cases of acrofacial dysostosis Rodriguez type, a syndrome characterized by mandibular hypoplasia, upper and lower extremity phocomelia, and oligodactyly of the upper limbs. More recently, haploinsufficiency of the SF3B4 gene has been identified as the cause of both Nager and Rodriguez syndrome, leading many to believe that Rodriguez syndrome represents a more severe end of a Nager syndrome spectrum. An SF3B4 mutation was found in our patient, prompting a review of the previous known cases of Rodriguez syndrome, which revealed no clustering of SF3B4 mutations, and four cases of Rodriguez syndrome with mutations identical to those in cases of Nager syndrome. Rodriguez syndrome was previously thought of as a lethal acrofacial dysostosis distinct from Nager syndrome. A number of more mild cases, as well as our case, intermediate between the two phenotypes, illustrate that Rodriguez syndrome is a severe manifestation of Nager syndrome, and is not lethal with aggressive medical care.

11.
J Autism Dev Disord ; 49(5): 2184-2202, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30783897

RESUMO

The presence of multiple dysmorphic features in some children with autism spectrum disorder (ASD) might identify distinct ASD phenotypes and serve as potential markers for understanding causes and prognoses. To evaluate dysmorphology in ASD, children aged 3-6 years with ASD and non-ASD population controls (POP) from the Study to Explore Early Development were evaluated using a novel, systematic dysmorphology review approach. Separate analyses were conducted for non-Hispanic White, non-Hispanic Black, and Hispanic children. In each racial/ethnic group, ~ 17% of ASD cases were Dysmorphic compared with ~ 5% of POP controls. The ASD-POP differential was not explained by known genetic disorders or birth defects. In future epidemiologic studies, subgrouping ASD cases as Dysmorphic vs. Non-dysmorphic might help delineate risk factors for ASD.


Assuntos
Transtorno do Espectro Autista/diagnóstico , Anormalidades Craniofaciais/complicações , Facies , Fenótipo , Transtorno do Espectro Autista/classificação , Transtorno do Espectro Autista/complicações , Criança , Desenvolvimento Infantil , Pré-Escolar , Grupos Étnicos , Feminino , Humanos , Masculino
12.
Am J Med Genet A ; 179(3): 381-385, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30582277

RESUMO

The 22q11.2 deletion syndrome (22q11.2DS) involves multiple organ systems with variable phenotypic expression. Genitourinary tract abnormalities have been noted to be present in up to 30-40% of patients. At our institution, an internationally recognized, comprehensive, and multidisciplinary 22q11.2DS care center has been providing care to these children. We sought to report on the incidence of genitourinary tract anomalies in this large cohort and, therefore, retrospectively reviewed all patients who underwent a complete evaluation from 1992 to March 2017. We identified all children with any genital or urinary tract anomaly. For all children with a diagnosis of hydronephrosis, the underlying etiology was determined, when possible. Overall, 1,073 of 1,267 children with 22q11.2DS underwent renal evaluations at our institution. Hundered Sixty-Two (15.1%) children had structural abnormalities of their kidneys/urinary tracts. The majority of children with hydronephrosis (63%) had isolated upper tract dilation without any additional diagnoses. Boys were significantly more likely to be diagnosed with a genital abnormality than girls (7.7 vs. 0.5%, p < 0.001). Of the 649 boys in the entire cohort, 24 (3.7%) had cryptorchidism and 24 (3.7%) had hypospadias, which was noted to be mild in all except one boy. Overall, findings of hydronephrosis, unilateral renal agenesis, and multicystic dysplastic kidney occur at higher rates than expected in the general population. Given these findings, in addition to routine physical examination, we believe that all patients with 22q11.2DS warrant screening RBUS at time of diagnosis.

13.
Am J Med Genet A ; 176(10): 2167-2171, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30380188

RESUMO

Hypocalcemia has been reported in ~50% of patients 22q11.2DS and calcium regulation is known to play a role in neuronal development and synaptic plasticity. Because calcium ions play a role in neuronal function and development, we hypothesized that hypocalcemia would be associated with adverse effects on full scale IQ index (FSIQ) in patients with 22q11.2DS. A retrospective chart review cataloguing the presence or absence of hypocalcemia in 1073 subjects with a laboratory confirmed chromosome 22q11.2 deletion evaluated at the Children's Hospital of Philadelphia was conducted. 852/1073 patients had an endocrinology evaluation with laboratory confirmed calcium levels. 466/852 (54.7%) had a diagnosis of hypocalcemia. 265/1073 subjects ranging from 0 to 51 years of age had both calcium levels measured and a neuropsychological evaluation yielding a FSIQ. The mean FSIQ for 146/265 patients with hypocalcemia was 77.09 (SD = 13.56) and the mean FSIQ for 119/265 patients with normocalcemia was 77.27 (SD = 14.25). The distribution of patients with intellectual disability (ID) (FSIQ<69), borderline IQ (FSIQ 70-79), and average IQ (FSIQ>80) between the hypocalcemic and normocalcemic groups was not statistically significant (χ2 = 0.2676, p = 0.8748). Neonatal hypocalcemic seizures were not found to be associated with ID. We found no difference in FSIQ between the hypocalcemic and non-hypocalcemic patients with 22q11.2DS. As our findings differ from a previous report in adult subjects, we speculate that this may reflect a potential benefit from early treatment of hypocalcemia and may support early 22q11.2 deletion detection in order to offer prompt diagnosis and subsequent treatment of hypocalcemia.

14.
Am J Med Genet A ; 176(10): 2058-2069, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30380191

RESUMO

22q11.2 deletion syndrome (22q11.2DS) is a disorder caused by recurrent, chromosome-specific, low copy repeat (LCR)-mediated copy-number losses of chromosome 22q11. The Children's Hospital of Philadelphia has been involved in the clinical care of individuals with what is now known as 22q11.2DS since our initial report of the association with DiGeorge syndrome in 1982. We reviewed the medical records on our continuously growing longitudinal cohort of 1,421 patients with molecularly confirmed 22q11.2DS from 1992 to 2018. Most individuals are Caucasian and older than 8 years. The mean age at diagnosis was 3.9 years. The majority of patients (85%) had typical LCR22A-LCR22D deletions, and only 7% of these typical deletions were inherited from a parent harboring the deletion constitutionally. However, 6% of individuals harbored other nested deletions that would not be identified by traditional 22q11.2 FISH, thus requiring an orthogonal technology to diagnose. Major medical problems included immune dysfunction or allergies (77%), palatal abnormalities (67%), congenital heart disease (64%), gastrointestinal difficulties (65%), endocrine dysfunction (>50%), scoliosis (50%), renal anomalies (16%), and airway abnormalities. Median full-scale intelligence quotient was 76, with no significant difference between individuals with and without congenital heart disease or hypocalcemia. Characteristic dysmorphic facial features were present in most individuals, but dermatoglyphic patterns of our cohort are similar to normal controls. This is the largest longitudinal study of patients with 22q11.2DS, helping to further describe the condition and aid in diagnosis and management. Further surveillance will likely elucidate additional clinically relevant findings as they age.

15.
Am J Med Genet B Neuropsychiatr Genet ; 177(8): 765-773, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30444066

RESUMO

Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with impairment in multiple domains of cognition and risk for several psychiatric disorders. Musical auditory processing is highly heritable, and is impaired in individuals with schizophrenia and other neurodevelopmental disorders, but has never been studied in 22q11DS, notwithstanding anecdotal evidence of its sparing. We aimed to characterize musical auditory processing in 22q11DS and explore potential relationships with other cognitive domains, musical engagement, and psychiatric disorders. The Distorted Tunes Task and Global Musical Sophistication Index were used to assess pitch discrimination and general musical engagement in 58 individuals with 22q11DS aged 8-29 years. Psychopathology was assessed with sections from the modified Schedule for Affective Disorders and Schizophrenia for School-Age Children and the Structured Interview for Prodromal Syndromes. The Penn computerized neurocognitive battery (CNB) examined four domains of cognition (executive functioning, episodic memory, complex cognition, and social cognition). Significant musical auditory processing impairment and reduced musical engagement were found in individuals with 22q11DS. However, deficits in musical auditory processing were not associated with reduced musical engagement. After covarying for age and sex, episodic memory and overall CNB performance accuracy were significantly related to performance in musical auditory processing. There were no relationships between musical auditory processing and presence of any psychiatric diagnoses. Individuals with 22q11DS experience significant deficits in musical auditory processing and reduced musical engagement. Pitch discrimination is associated with overall cognitive ability, but appears to be largely independent of psychiatric illness.

16.
Am J Med Genet A ; 176(10): 2140-2145, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30365873

RESUMO

Children with 22q11.2 deletion syndrome often come to medical attention due to signs and symptoms of neurologic dysfunction. It is imperative to understand the expected neurologic development of patients with this diagnosis in order to be alert for the potential neurologic complications, including cortical malformations, tethered cord, epilepsy, and movement disorders. We present an update of brain imaging findings from the CHOP 22q and You Center, a review of the current literature, and our current management practices for neurological issues.

17.
Am J Med Genet A ; 176(10): 2099-2103, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30277015

RESUMO

Hypocalcemia is one of the cardinal features of the chromosome 22q11.2 deletion syndrome (22q11.2DS), the most common cause of DiGeorge syndrome. Hypocalcemia and other features of 22q11.2DS including congenital heart disease (CHD) are primarily ascribed to problems with morphogenesis and function of the pharyngeal arch system derivatives including the parathyroid glands, the aortic arch, and the cardiac outflow tract. In light of the aforementioned embryology, we hypothesized that hypocalcemia would be identified more frequently in those patients with 22q11.2DS and CHD. We conducted a retrospective IRB approved chart review on 1,300 subjects with 22q11.2DS evaluated at the Children's Hospital of Philadelphia. χ2 test was used to evaluate the statistical significance of differences in hypocalcemia between the two groups. Eight hundred fifty-two patients had calcium levels available for review. Of these, 466 (54.69%) had a history of hypocalcemia and 550 (64.55%) had CHD. Of those with CHD, 343 (62.36%) had a history of hypocalcemia, and of those without CHD, only 123 (40.73%) had a history of hypocalcemia. Thus, the frequency of diagnosed hypocalcemia was greater in patients with 22q11.2DS and CHD as compared to those without CHD (p < .001). We also analyzed age of onset of hypocalcemia and found that 66.47% of CHD/hypocalcemia group had neonatal/infantile hypocalcemia versus 43.09% in the non-CHD/hypocalcemia group. In our large cohort of patients with 22q11.2DS, the prevalence of diagnosed hypocalcemia is elevated among patients with CHD, in whom it is more likely to be diagnosed during the neonatal/infancy period.

18.
Am J Med Genet A ; 176(10): 2203-2214, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30244528

RESUMO

22q11.2 deletion syndrome (DS) is the most frequent copy number variant (CNV) affecting ~1/1,000 fetuses and ~1/2,000-4,000 children, resulting in recognizable but variable findings across multiple organ systems. Patients with atypical features should prompt consideration of coexisting diagnoses due to additional genome-wide mutations, CNVs, or mutations/CNVs on the other allele, unmasking autosomal recessive conditions. Importantly, a dual diagnosis compounds symptoms and impacts management. We previously reported seven patients with 22q11.2DS and: SCID, Trisomy 8 mosaicism, Bernard-Soulier, and CEDNIK syndromes. Here we present six additional unreported patients with 22q11.2DS and concurrent diagnoses. Records on 1,422 patients with 22q11.2DS, identified via FISH, microarray, or MLPA, followed in our 22q and You Center at the Children's Hospital of Philadelphia (CHOP) were reviewed to identify a dual diagnosis. In addition to our seven previously reported cases, we identified an additional six with 22q11.2DS and another coexisting condition identified via: molecular/cytogenetic studies, newborn screening, coagulation factor studies, or enzyme testing; these include CHARGE syndrome (CHD7 mutation), cystic fibrosis, a maternally inherited 17q12 deletion, G6PD deficiency, von Willebrand disease, and 1q21.1 deletion, resulting in an incidence of dual diagnoses at our center of 0.9%. The range of dual diagnoses identified in our cohort is notable, medically actionable, and may alter long-term outcome and recurrence risk counseling. Thus, our findings may support testing patients with 22q11.2DS using a combination of microarray, mutational analysis of the other allele/WES, to ensure appropriate personalized care, as formulating medical management decisions hinges on establishing the correct diagnoses in their entirety.

19.
Am J Med Genet A ; 176(9): 1890-1896, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30152016

RESUMO

Xia-Gibbs syndrome (XGS) is a recently described neurodevelopmental disorder due to heterozygous loss-of-function AHDC1 mutations. XGS is characterized by global developmental delay, intellectual disability, hypotonia, and sleep abnormalities. Here we report the clinical phenotype of five of six individuals with XGS identified prospectively at the Children's Hospital of Philadelphia, a tertiary children's hospital in the USA. Although all five patients demonstrated common clinical features characterized by developmental delay and characteristic facial features, each of our patients showed unique clinical manifestations. Patient one had craniosynostosis; patient two had sensorineural hearing loss and bicuspid aortic valve; patient three had cutis aplasia; patient four had soft, loose skin; and patient five had a lipoma. Differential diagnoses considered for each patient were quite broad, and included craniosynostosis syndromes, connective tissue disorders, and mitochondrial disorders. Exome sequencing identified a heterozygous, de novo AHDC1 loss-of-function mutation in four of five patients; the remaining patient has a 357kb interstitial deletion of 1p36.11p35.3 including AHDC1. Although it remains unknown whether these unique clinical manifestations are rare symptoms of XGS, our findings indicate that the diagnosis of XGS should be considered even in individuals with additional non-neurological symptoms, as the clinical spectrum of XGS may involve such non-neurological manifestations. Adding to the growing literature on XGS, continued cohort studies are warranted in order to both characterize the clinical spectrum of XGS as well as determine standard of care for patients with this diagnosis.

20.
Front Immunol ; 9: 1715, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30087679

RESUMO

Located contiguously on the long arm of the second chromosome are gene paralogs encoding the immunoglobulin-family co-activation receptors CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). CD28 and CTLA4 share the same B7 ligands yet each provides opposing proliferative signals to T cells. Herein, we describe for the first time two unrelated subjects with coexisting CD28 and CTLA4 haploinsufficiency due to heterozygous microdeletions of chromosome 2q. Although their clinical phenotype, multi-organ inflammatory disease, is superficially similar to that of CTLA4 haploinsufficient autoimmune lymphoproliferative syndrome type V (ALPS5) patients, we demonstrate our subjects' underlying immunopathology to be distinct. Unlike ALPS5 T cells which hyperproliferate to T-cell receptor-mediated activation and infiltrate organs, T cells from our subjects are hypoproliferative and do not. Instead of T cell infiltrates, biopsies of affected subject tissues demonstrated infiltrates of lineage negative lymphoid cells. This histologic feature correlated with significant increases in circulating type 3 innate lymphoid cells (ILC3s) and ILC3 cytokines, interleukin 22, and interleukin-17A. CTLA4-Ig monotherapy, which we trialed in one subject, was remarkably effective in controlling inflammatory diseases, normalizing ILC3 frequencies, and reducing ILC3 cytokine concentrations.

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