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1.
BMC Med Genet ; 21(Suppl 1): 156, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-33092543

RESUMO

BACKGROUND: Hereditary ophthalmic pathology is a genetically heterogeneous group of diseases that occur either as an isolated eye disorder or as a symptom of hereditary syndromes (chromosomal or monogenic). Thus, a diagnostic search in some cases of ophthalmic pathology can be time- and cost-consuming. The most challenging situation can arise when prenatal diagnosis is needed during an ongoing pregnancy. CASE PRESENTATION: A family was referred to the Research Centre for Medical Genetics (RCMG) for childbirth risk prognosis at 7-8 week of gestation because a previous child, a six-year-old boy, has congenital aniridia, glaucoma, retinal detachment, severe psychomotor delay, and lack of speech and has had several ophthalmic surgeries. The affected child had been previously tested for PAX6 mutations and 11p13 copy number variations, which revealed no changes. Considering the lack of pathogenic changes and precise diagnosis for the affected boy, NGS sequencing of clinically relevant genes was performed for the ongoing pregnancy; it revealed a novel hemizygous substitution NM_000266.3(NDP):c.385G > T, p.(Glu129*), in the NDP gene, which is associated with Norrie disease (OMIM #310600). Subsequent Sanger validation of the affected boy and his mother confirmed the identified substitution inherited in X-linked recessive mode. Amniotic fluid testing revealed the fetus was hemizygous for the variant and lead to the decision of the family to interrupt the pregnancy. Complications which developed during the termination of pregnancy required hysterectomy due to medical necessity. CONCLUSIONS: Clinical polymorphism of hereditary ophthalmic pathology can severely complicate establishment of an exact diagnosis and make it time- and cost-consuming. NGS appears to be the method-of-choice in complicated cases, and this could substantially hasten the establishment of a diagnosis and genetic risk estimation.


Assuntos
Cegueira/congênito , Proteínas do Olho/genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Proteínas do Tecido Nervoso/genética , Doenças do Sistema Nervoso/diagnóstico , Diagnóstico Pré-Natal/métodos , Degeneração Retiniana/diagnóstico , Espasmos Infantis/diagnóstico , Substituição de Aminoácidos , Cegueira/diagnóstico , Cegueira/genética , Olho/patologia , Feminino , Genes Ligados ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Doenças do Sistema Nervoso/genética , Gravidez , Degeneração Retiniana/genética , Espasmos Infantis/genética , Sequenciamento Completo do Exoma
2.
BMC Med Genet ; 21(1): 209, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087045

RESUMO

BACKGROUND: Epilepsy with intellectual disability limited to females (Epileptic encephalopathy, early infantile, 9; EIEE9) is a rare early infantile epileptic encephalopathy characterized by an unusual X-linked inheritance: females with heterozygous mutations are affected, while hemizygous males are not. CASE PRESENTATION: We describe the clinical and molecular characteristics of 2 Russian patients with EIEE9 (females, ages 3 years and 7 years). In these patients seizures developed at the age of 3 years. Additionally, for our patients and for cases described in the literature we searched for a possible relationship between the type and localization of the mutation and the EIEE9 clinical phenotype. CONCLUSIONS: We identified two novel PCDH19 mutations in EIEE9 patients: a missense mutation in exon 1 (c.1236C > A, p.Asp412Glu) and a frameshift in exon 3 (c.2386_2387insGTCT, p.Thr796fs). We conclude that the age of seizure onset and the presence of intellectual disability may depend not on the type and localization of PCDH19 mutations, but on the X-inactivation status. The study also highlights the need to screen for EIEE9 among young female epilepsy patients.


Assuntos
Caderinas/genética , Epilepsia/genética , Mutação da Fase de Leitura , Doenças Genéticas Ligadas ao Cromossomo X/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto , Idade de Início , Caderinas/deficiência , Criança , Pré-Escolar , Epilepsia/diagnóstico , Epilepsia/patologia , Feminino , Expressão Gênica , Genes Ligados ao Cromossomo X , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Linhagem , Sequenciamento Completo do Exoma , Inativação do Cromossomo X
4.
BMC Med Genet ; 21(1): 131, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32552675

RESUMO

BACKGROUND: X-linked agammaglobulinaemia (XLA) is a rare immunodeficiency disease for which recurrent severe infection is the major clinical symptom. BTK is the main causative gene, with X chromosome recessive inheritance. However, the mutations reported to date do not fully explain the disorder. METHODS: We detected the percentage of CD19+ B cells and serum immunoglobulin (IgG, IgA, and IgM) levels by flow cytometry and rate scatter immunoturbidimetry, and investigated the BTK mutation profile in 22 XLA patients using Sanger sequencing and real-time PCR . RESULTS: We evaluated the clinical symptoms of 22 XLA patients and investigated genetic mutations present, identifying six novel mutations in the BTK gene: 2 missense mutations (c.23G > T and c.112 T > C), 2 frameshift mutations (c.522_523insC and c.1060delA), 1 large deletion (deletion of exon 2 to 5), and 1 splice-site mutation (c.1631 + 2 T > C). Prenatal diagnoses were performed in six families (F10, F11, F15, F18, F20 and F21), with the following results: the male fetus in Family 10 (F10) did not carry the c.922_923delGA mutation; the male fetus in Family 15 (F15) did not carry the c.1631 + 1G > T splicing mutation; the female fetus in Family 20 (F20) did not carry the c.1931 T > C mutation; the female fetus in Family 21 (F21) did not carry the large deletion mutation. Hence, these four fetuses are not likely to develop XLA. Male fetuses with c.1060delA and c.1684C > T mutations were identified in Family 11 and Family 18, respectively. The pregnant woman in F18 chose to terminate the pregnancy, whereas the pregnant woman in F11 chose to continue the pregnancy. CONCLUSION: We confirmed the diagnosis of 22 XLA patients from 22 unrelated families and detected six new pathogenic mutations. Prenatal diagnosis was performed in six families. Early genetic diagnosis and routine lifelong immunoglobulin replacement therapy can prevent and treat infections in XLA children, saving their lives.


Assuntos
Tirosina Quinase da Agamaglobulinemia/genética , Agamaglobulinemia/enzimologia , Agamaglobulinemia/genética , Doenças Genéticas Ligadas ao Cromossomo X/enzimologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação/genética , Diagnóstico Pré-Natal , Agamaglobulinemia/diagnóstico , Sequência de Bases , Estudos de Casos e Controles , Criança , Pré-Escolar , China , Análise Mutacional de DNA , Família , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem
9.
Adv Ther ; 37(Suppl 2): 29-37, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32236876

RESUMO

Rare diseases are heterogeneous life-threatening or seriously debilitating conditions that affect < 1 in 2000 individuals, and most have a genetic component. The diagnostic process is usually based on classic clinical practices, such as physical examination, personal and family history (inheritance pattern), laboratory tests and image studies, but diagnosis can be delayed several years after the initiation of symptoms. The advances in molecular genetics that have taken place in recent years have led to an important shift in medical practice and in its approach to the diagnosis and treatment of many rare diseases. The objective of this review is to promote a better understanding of the mechanisms underlying genetic diseases in humans and the tools available for their diagnosis. A practical example of X-linked hypophosphataemic rickets is described.


Assuntos
Raquitismo Hipofosfatêmico Familiar/diagnóstico , Raquitismo Hipofosfatêmico Familiar/genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Predisposição Genética para Doença , Biologia Molecular/métodos , Doenças Raras/diagnóstico , Doenças Raras/genética , Humanos
10.
Adv Ther ; 37(Suppl 2): 89-94, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32236877

RESUMO

Rickets and osteomalacia are two related conditions linked by the lack of mineralization of bone tissue due to a disturbance of calcium and phosphate homeostasis. Some of the most characteristic features of rickets are skeletal deformities, fractures, linear and continuous periosteal reaction, and enlargement of the metaphyseal space in an irregular and frayed form. However, these radiological findings are not exclusive to these diseases, but may also originate in children who were born prematurely or in those who have suffered physical abuse or an accident. Hence, it is important to establish a differential diagnosis. All these observations can be evidenced by radiological images using a simple X-ray. The aim of this article is to show the main radiological findings that can be found in rickets and how to establish a differential diagnosis of X-linked hypophosphataemic (XLH) rickets.


Assuntos
Diagnóstico Diferencial , Raquitismo Hipofosfatêmico Familiar/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Lâmina de Crescimento/diagnóstico por imagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Raios X
11.
Arch Soc Esp Oftalmol ; 95(4): 201-204, 2020 Apr.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-32057558

RESUMO

The neonate has a horizontal diameter of the cornea, usually up to 10mm with growth up to 2mm in the first 2 years of life. We report a case of megalocornea, a rare, recessive, X-linked disorder in a 3-month-old child, seeking to review what the medical literature brings information about the condition, as well as diagnostic and follow-up parameters, of its main differential diagnoses.


Assuntos
Oftalmopatias Hereditárias , Doenças Genéticas Ligadas ao Cromossomo X , Córnea/anatomia & histologia , Oftalmopatias Hereditárias/diagnóstico , Oftalmopatias Hereditárias/etiologia , Oftalmopatias Hereditárias/terapia , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/etiologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Lactente , Masculino
13.
Genes (Basel) ; 11(2)2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-32013026

RESUMO

Inherited retinal dystrophies (IRDs) are characterized by high clinical and genetic heterogeneity. A precise characterization is desirable for diagnosis and has impact on prognosis, patient counseling, and potential therapeutic options. Here, we demonstrate the effectiveness of the combination of in-depth retinal phenotyping and molecular genetic testing in complex pedigrees with different IRDs. Four affected Caucasians and two unaffected relatives were characterized including multimodal retinal imaging, functional testing, and targeted next-generation sequencing. A considerable intrafamilial phenotypic and genotypic heterogeneity was identified. While the parents of the index family presented with rod-cone dystrophy and ABCA4-related retinopathy, their two sons revealed characteristics in the spectrum of incomplete congenital stationary night blindness and ocular albinism, respectively. Molecular testing revealed previously described variants in RHO, ABCA4, and MITF as well as a novel variant in CACNA1F. Identified variants were verified by intrafamilial co-segregation, bioinformatic annotations, and in silico analysis. The coexistence of four independent IRDs caused by distinct mutations and inheritance modes in one pedigree is demonstrated. These findings highlight the complexity of IRDs and underscore the need for the combination of extensive molecular genetic testing and clinical characterization. In addition, a novel variant in the CACNA1F gene is reported associated with incomplete congenital stationary night blindness.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Albinismo Ocular/diagnóstico , Canais de Cálcio Tipo L/genética , Distrofias de Cones e Bastonetes/diagnóstico , Oftalmopatias Hereditárias/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Fator de Transcrição Associado à Microftalmia/genética , Miopia/diagnóstico , Cegueira Noturna/diagnóstico , Adolescente , Albinismo Ocular/genética , Criança , Distrofias de Cones e Bastonetes/genética , Oftalmopatias Hereditárias/genética , Feminino , Angiofluoresceinografia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Miopia/genética , Cegueira Noturna/genética , Pais , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
14.
Ophthalmology ; 127(4): 492-500, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31937464

RESUMO

PURPOSE: To evaluate structural grading and quantitative segmentation of foveal hypoplasia using handheld OCT, versus preferential looking (PL), as predictors of future vision in preverbal children with infantile nystagmus. DESIGN: Longitudinal cohort study. PARTICIPANTS: Forty-two patients with infantile nystagmus (19 with albinism, 17 with idiopathic infantile nystagmus, and 6 with achromatopsia) were examined. METHODS: Spectral-domain handheld OCT was performed in preverbal children up to 36 months of age. Foveal tomograms were graded using our 6-point grading system for foveal hypoplasia and were segmented for quantitative analysis: photoreceptor length, outer segment (OS) length, and foveal developmental index (FDI; a ratio of inner layers versus total foveal thickness). Patients were followed up until they could perform chart visual acuity (VA) testing. Data were analyzed using linear mixed regression models. Visual acuity predicted by foveal grading was compared with prediction by PL, the current gold standard for visual assessment in infants and young children. MAIN OUTCOME MEASURES: Grade of foveal hypoplasia, quantitative parameters (photoreceptor length, OS length, FDI), and PL VA were obtained in preverbal children for comparison with future chart VA outcomes. RESULTS: We imaged 81 eyes from 42 patients with infantile nystagmus of mean age 19.8 months (range, 0.9-33.4 months; standard deviation [SD], 9.4 months) at the first handheld OCT scan. Mean follow-up was 44.1 months (range, 18.4-63.2 months; SD, 12.0 months). Structural grading was the strongest predictor of future VA (grading: r = 0.80, F = 67.49, P < 0.0001) compared with quantitative measures (FDI: r = 0.74, F = 28.81, P < 0.001; OS length: r = 0.65; F = 7.94, P < 0.008; photoreceptor length: r = 0.65; F = 7.94, P < 0.008). Preferential looking was inferior to VA prediction by foveal grading (PL: r = 0.42, F = 3.12, P < 0.03). CONCLUSIONS: Handheld OCT can predict future VA in infantile nystagmus. Structural grading is a better predictor of future VA than quantitative segmentation and PL testing. Predicting future vision may avert parental anxiety and may optimize childhood development.


Assuntos
Anormalidades do Olho/patologia , Fóvea Central/anormalidades , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Nistagmo Congênito/diagnóstico , Transtornos da Visão/diagnóstico , Albinismo Oculocutâneo/diagnóstico , Albinismo Oculocutâneo/fisiopatologia , Pré-Escolar , Defeitos da Visão Cromática/diagnóstico , Defeitos da Visão Cromática/fisiopatologia , Anormalidades do Olho/classificação , Feminino , Seguimentos , Fóvea Central/diagnóstico por imagem , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Humanos , Lactente , Estudos Longitudinais , Masculino , Nistagmo Congênito/fisiopatologia , Estudos Prospectivos , Tomografia de Coerência Óptica , Transtornos da Visão/fisiopatologia , Acuidade Visual/fisiologia
15.
Eur J Ophthalmol ; 30(1): 147-154, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30541351

RESUMO

PURPOSE: To study electroretinograms in infantile nystagmus syndrome associated with idiopathic infantile nystagmus, optic nerve hypoplasia, and albinism. METHODS: A total of 30 children with idiopathic infantile nystagmus, 18 with optic nerve hypoplasia, and 18 with albinism were studied. Three electroretinogram protocols were applied according to child's age: 58 (mean: 2.0 years) were recorded with skin electrode to Great Ormond Street Hospital protocol, 11 (mean: 5.3 years) with skin electrode to International Society for Clinical Electrophysiology of Vision protocol, and 7 children (mean: 12.2 years) with HK electrode to International Society for Clinical Electrophysiology of Vision protocol. The electroretinograms were compared to those of age-matched controls. RESULTS: Electroretinogram waveforms in idiopathic infantile nystagmus, optic nerve hypoplasia, and albinism were comparable to controls in all protocols. Electroretinogram amplitudes in idiopathic infantile nystagmus group showed increased white scotopic and photopic electroretinograms in 26 children (skin electrode to Great Ormond Street Hospital protocol), no difference to the controls in 3 children (skin electrode to International Society for Clinical Electrophysiology of Vision protocol), and increased rod electroretinogram in 3 children (HK electrode to International Society for Clinical Electrophysiology of Vision protocol). Optic nerve hypoplasia group showed increased white scotopic, photopic, and blue electroretinograms in 15 children (skin electrode to Great Ormond Street Hospital protocol); increased 30-Hz electroretinogram in 3 children (HK electrode to International Society for Clinical Electrophysiology of Vision protocol); and reduced combined rod-cone, cone, and 30-Hz electroretinograms in 3 children (skin electrode to International Society for Clinical Electrophysiology of Vision protocol). Albinism group showed increased white scotopic, photopic, and 30-Hz electroretinograms in 17 children (skin electrode to Great Ormond Street Hospital protocol), while it showed reduced cone and 30-Hz electroretinograms in 5 children (skin electrode to International Society for Clinical Electrophysiology of Vision protocol). Implicit times were shorter in albinism. CONCLUSION: Electroretinogram waveforms in idiopathic infantile nystagmus, optic nerve hypoplasia, and albinism were normal with mostly increased electroretinograms, while reduced electroretinograms did not show a specific pattern as in early-onset retinal dystrophies.


Assuntos
Anormalidades Múltiplas , Albinismo/fisiopatologia , Eletrorretinografia/métodos , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Nistagmo Congênito/fisiopatologia , Hipoplasia do Nervo Óptico/fisiopatologia , Albinismo/diagnóstico , Criança , Pré-Escolar , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Humanos , Lactente , Masculino , Nistagmo Congênito/diagnóstico , Hipoplasia do Nervo Óptico/diagnóstico
16.
Adv Ther ; 37(2): 770-784, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31865548

RESUMO

INTRODUCTION: Capturing the patient experience of living with a rare disease such as X-linked hypophosphataemia (XLH) is critical for a holistic understanding of the burden of a disease. The complexity of the disease coupled with the limited population makes elicitation of the patient burden methodologically challenging. This study used qualitative information direct from patient and caregiver statements to assess the burden of XLH. METHODS: A thematic analysis was conducted on statements received during a National Institute for Health and Care Excellence (NICE) online public open consultation from 15 June to 6 July 2018. Researchers and clinical experts generated themes and codes based on expected aspects of XLH burden. Statements were independently coded by two reviewers, adding additional codes as required, and analysed by frequency and co-reporting across age groups. RESULTS: The majority of responses were submitted from UK-based patients with some from the USA and Australia, and the statements related to children, adolescents and adults. The findings suggest that the greatest burden experienced by children is associated with conventional therapy, co-reported with dosing regimen, adherence, distress and pain. During adolescence, the burden becomes increasingly complex and multi-factorial, with an increasing psychological burden. In adults, conventional therapy co-reported with bone deformity and orthopaedic surgery, as well as pain, mobility, fatigue and dental problems, featured highly. DISCUSSION: Whilst our study was opportunistic in nature, it has highlighted the clear and distinctive evolution of the burden of XLH, transitioning from being therapy-oriented in childhood to multi-factorial in adolescence, and finally to adulthood with its high impact on need for other interventions, function and mobility. This qualitative thematic analysis enhances the understanding of the symptom and treatment burden of XLH.


Assuntos
Cuidadores/psicologia , Efeitos Psicossociais da Doença , Raquitismo Hipofosfatêmico Familiar/psicologia , Família/psicologia , Doenças Genéticas Ligadas ao Cromossomo X/psicologia , Pacientes/psicologia , Qualidade de Vida/psicologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Criança , Pré-Escolar , Raquitismo Hipofosfatêmico Familiar/diagnóstico , Raquitismo Hipofosfatêmico Familiar/terapia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Reino Unido/epidemiologia , Estados Unidos/epidemiologia , Adulto Jovem
17.
Am J Med Genet A ; 182(3): 498-503, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31840929

RESUMO

Renpenning syndrome (OMIM: 309500) is a rare X-linked disorder that causes intellectual disability, microcephaly, short stature, a variety of eye anomalies, and characteristic craniofacial features. This condition results from pathogenic variation of PQBP1, a polyglutamine-binding protein involved in transcription and pre-mRNA splicing. Renpenning syndrome has only been reported in affected males. Carrier females do not usually have clinical features, and in reported families with Renpenning syndrome, most female carriers exhibit favorable skewing of X-chromosome inactivation. We describe a female with syndromic features typical of Renpenning syndrome. She was identified by exome sequencing to have a de novo heterozygous c.459_462delAGAG mutation in PQBP1 (Xp11.23), affecting the AG hexamer in exon 4, which is the most common causative mutation in this syndrome. Streaky hypopigmentation of the skin was observed, supporting a hypothesized presence of an actively expressed, PQBP1 mutation-bearing X-chromosome in some cells. X-inactivation studies on peripheral blood cells demonstrated complete skewing in both the proband and her mother with preferential inactivation of the maternal X chromosome in the child. We demonstrated expression of the PQBP1 mutant transcript in leukocytes of the affected girl. Therefore, it is highly likely that the PQBP1 mutation arose from the paternal X chromosome.


Assuntos
Anormalidades Múltiplas/genética , Paralisia Cerebral/genética , Proteínas de Ligação a DNA/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Retardo Mental Ligado ao Cromossomo X/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Paralisia Cerebral/diagnóstico , Paralisia Cerebral/patologia , Criança , Cromossomos Humanos X/genética , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Masculino , Retardo Mental Ligado ao Cromossomo X/diagnóstico , Retardo Mental Ligado ao Cromossomo X/patologia , Mutação/genética , Inativação do Cromossomo X/genética
18.
Am J Med Genet A ; 182(3): 513-520, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31880405

RESUMO

We describe an 11-year old boy with severe global developmental delays, failure to thrive and growth retardation, refractory seizures with recurrent status epilepticus, hypogammaglobulinemia, hypergonadotropic hypogonadism, and duodenal strictures. He had facial and skin findings compatible with trichothiodystrophy, including sparse and brittle hair, thin eyebrows, and dry skin. Exome sequencing showed a hemizygous, truncating variant in RNF113A, c.903_910delGCAGACCA, predicting p.(Gln302fs*12), that was inherited from his mother. Although his clinical features overlap closely with features described in the two previously reported male first cousins with RNF113A loss of function mutations, the duodenal strictures seen in this patient have not been reported. Interestingly, the patient's mother had short stature and 100% skewed X-inactivation as seen in other obligate female carriers. A second male with developmental delays, microcephaly, seizures, ambiguous genitalia, and facial anomalies that included sparse and brittle hair, thin eyebrows and dry skin was recently reported to have c.897_898delTG, predicting p.(Cys299*) in RNF113A and we provide additional clinical details for this patient. This report further supports deleterious variants in RNF113A as a cause of a novel trichothiodystrophy syndrome.


Assuntos
Proteínas de Ligação a DNA/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Predisposição Genética para Doença , Síndromes de Tricotiodistrofia/genética , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Masculino , Mutação/genética , Síndromes de Tricotiodistrofia/diagnóstico , Síndromes de Tricotiodistrofia/patologia , Inativação do Cromossomo X/genética
19.
BMC Neurol ; 19(1): 320, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31830942

RESUMO

BACKGROUND: X-linked agammaglobulinaemia (XLA) is a rare inherited primary immunodeficiency disease characterized by the B cell developmental defect, caused by mutations in the gene coding for Bruton's tyrosine kinase (BTK), which may cause serious recurrent infections. The diagnosis of XLA is sometimes challenging because a few number of patients have higher levels of serum immunoglobulins than expected. In this study, we reported an atypical case with recurrent meningitis, delayed diagnosis with XLA by genetic analysis at the second episode of meningitis at the age of 8 years. CASE REPORT: An 8-year-old Chinese boy presented with fever, dizziness and recurrent vomiting for 3 days. The cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) results were suggestive of bacterial meningoencephalitis, despite the negative gram staining and cultures of the CSF. The patient was treated with broad-spectrum antibiotics and responded well to the treatment. He had history of another episode of acute pneumococci meningitis 4 years before. The respective level of Immunoglobulin G (IgG), Immunoglobulin A (IgA) and Immunoglobulin M (IgM) was 4.85 g/L, 0.93 g/L and 0.1 g/L at 1st episode, whereas 1.9 g/L, 0.27 g/L and 0 g/L at second episode. The B lymphocytes were 0.21 and 0.06% of peripheral blood lymphocytes at first and second episode respectively. Sequencing of the BTK coding regions showed that the patient had a point mutation in the intron 14, hemizyous c.1349 + 5G > A, while his mother had a heterozygous mutation. It was a splice site mutation predicted to lead to exon skipping and cause a truncated BTK protein. CONCLUSION: Immunity function should be routinely checked in patients with severe intracranial bacterial infection. Absence of B cells even with normal level of serum immunoglobulin suggests the possibility of XLA, although this happens only in rare instances. Mutational analysis of BTK gene is crucial for accurate diagnosis to atypical patients with XLA.


Assuntos
Agamaglobulinemia/complicações , Agamaglobulinemia/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Encefalite Infecciosa/genética , Tirosina Quinase da Agamaglobulinemia/genética , Agamaglobulinemia/genética , Criança , Análise Mutacional de DNA , Diagnóstico Tardio , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Masculino , Mutação
20.
Medicine (Baltimore) ; 98(43): e17616, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651874

RESUMO

RATIONALE: Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is caused by mutations in GPC3 or in both GPC3 and GPC4. Physical manifestations of SGBS1 include fetal overgrowth and macrostomia, macroglossia. Subclinical hypothyroidism has never been reported in SGBS1 cases. PATIENT CONCERNS: An 8-days-old boy was referred to our hospital with persistent hypoglycemia and special facies. And the infant showed elevated levels of thyroid-stimulating hormone (TSH). Free T4 and free T3 were normal. DIAGNOSES: Definitive diagnosis of SGBS1 depends on clinical features and genetic testing. A nonsense mutation (c.1515C > A, p. Cys505*) was tested by whole-exome sequencing. INTERVENTIONS: Normal blood glucose levels were maintained with glucose infusions. Levothyroxine was given to the patient for treating subclinical hypothyroidism. OUTCOMES: The parents decided to abandon the treatment of the patient. We learned that the patient died of a lung infection by a telephone follow-up. LESSONS: Subclinical hypothyroidism could be added to the known clinical manifestations of SGBS1.


Assuntos
Arritmias Cardíacas/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Gigantismo/diagnóstico , Cardiopatias Congênitas/diagnóstico , Hipotireoidismo/diagnóstico , Deficiência Intelectual/diagnóstico , China , Diagnóstico Diferencial , Evolução Fatal , Humanos , Recém-Nascido , Masculino
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