Diagnostic Delay of Celiac Disease in Childhood.

Importance: The extent and factors associated with risk of diagnostic delay in pediatric celiac disease (CD) are poorly understood. Objectives: To investigate the diagnostic delay of CD in childhood, and to assess factors associated with this delay. Design, Setting, and Participants: Multicenter, retrospective, cross-sectional study (2010-2019) of pediatric (aged 0-18 years) patients with CD from 13 pediatric tertiary referral centers in Italy. Data were analyzed from January to June 2023. Main Outcomes and Measures: The overall diagnostic delay (ie, the time lapse occurring from the first symptoms or clinical data indicative of CD and the definitive diagnosis), further split into preconsultation and postconsultation diagnostic delay, were described. Univariable and multivariable linear regression models for factors associated with diagnostic delay were fitted. Factors associated with extreme diagnostic delay (ie, 1.5 × 75th percentile) and misdiagnosis were assessed. Results: A total of 3171 patients with CD were included. The mean (SD) age was 6.2 (3.9) years; 2010 patients (63.4%) were female; and 10 patients (0.3%) were Asian, 41 (1.3%) were Northern African, and 3115 (98.3%) were White. The median (IQR) overall diagnostic delay was 5 (2-11) months, and preconsultation and postconsultation diagnostic delay were 2 (0-6) months and 1 (0-3) month, respectively. The median (IQR) extreme overall diagnostic delay (586 cases [18.5%]) was 11 (5-131) months, and the preconsultation and postconsultation delays were 6 (2-120) and 3 (1-131) months, respectively. Patients who had a first diagnosis when aged less than 3 years (650 patients [20.5%]) showed a shorter diagnostic delay, both overall (median [IQR], 4 [1-7] months for patients aged less than 3 years vs 5 [2-12] months for others) and postconsultation (median [IQR], 1 [0-2] month for patients aged less than 3 years vs 2 [0-4] months for others). A shorter delay was registered in male patients, both overall (median [IQR], 4 [1-10] months for male patients vs 5 [2-12] months for female patients) and preconsultation (median [IQR], 1 [0-6] month for male patients vs 2 [0-6] months for female patients). Family history of CD was associated with lower preconsultation delay (odds ratio [OR], 0.59; 95% CI, 0.47-0.74) and lower overall extreme diagnostic delay (OR, 0.75; 95% CI, 0.56-0.99). Neurological symptoms (78 patients [21.5%]; OR, 1.35; 95% CI, 1.03-1.78), gastroesophageal reflux (9 patients [28.1%]; OR, 1.87; 95% CI, 1.02-3.42), and failure to thrive (215 patients [22.6%]; OR, 1.62; 95% CI, 1.31-2.00) showed a more frequent extreme diagnostic delay. A previous misdiagnosis (124 patients [4.0%]) was more frequently associated with gastroesophageal reflux disease, diarrhea, bloating, abdominal pain, constipation, fatigue, osteopenia, and villous atrophy (Marsh 3 classification). Conclusions and Relevance: In this cross-sectional study of pediatric CD, the diagnostic delay was rather short. Some factors associated with risk for longer diagnostic delay and misdiagnosis emerged, and these should be addressed in future studies.

[On the indiciary nature of the clinical method: an anthropological view of a published case study]. / Sobre el carácter indiciario del método clínico: una mirada antropológica a partir de un relato de caso publicado.

In this article we present a published case study as an object of reflection. On this basis, we carried out a partial reconstruction of the process of study and diagnostic elaboration of the Uruguay syndrome, showing the circumstances of the case, the selection and interpretation of "clues," and some of the details relevant to the clinical reasoning. Our starting point is the recognition of the narrative nature of clinical knowledge and of the clinical method as an indiciary method. The manuscript of the Uruguay syndrome has a narrative structure adjusted to the conventions of a scientific article, which gives lesser importance to the clinical method. We carried out diverse methodical encounters, mainly involving in-depth interviews with the authors of the manuscript and observation in their workplace. The text seeks to recover the histories of work based on the indiciary or semiotic model of knowledge, and recognize the importance of this model in medical practice.

Sobre el carácter indiciario del método clínico: una mirada antropológica a partir de un relato de caso publicado / On the indiciary nature of the clinical method: an anthropological view of a published case study

En este artículo presentamos un relato de caso publicado como objeto de reflexión, sobre el que se realizó una reconstrucción parcial del proceso de estudio y una elaboración diagnóstica del síndrome Uruguay, mostrando las circunstancias del caso, la selección e interpretaciones de "pistas", y algunos de los detalles que fueron relevantes en el raciocinio clínico. Nuestro punto de partida es el reconocimiento del carácter narrativo del conocimiento clínico y del método clínico como un método indiciario. El manuscrito del síndrome Uruguay presenta una estructura narrativa ajustada a las convenciones del artículo científico que pone al método clínico en un segundo plano. Nuestros encuentros metódicos fueron diversos y comprendieron, sobre todo, entrevistas en profundidad a los autores del manuscrito y observaciones en su lugar de trabajo. El texto propone recuperar las historias de trabajo basadas en un modelo de conocimiento indiciario o semiótico y reconocer su importancia en la práctica médica.

In this article we present a published case study as an object of reflection. On this basis, we carried out a partial reconstruction of the process of study and diagnostic elaboration of the Uruguay syndrome, showing the circumstances of the case, the selection and interpretation of "clues," and some of the details relevant to the clinical reasoning. Our starting point is the recognition of the narrative nature of clinical knowledge and of the clinical method as an indiciary method. The manuscript of the Uruguay syndrome has a narrative structure adjusted to the conventions of a scientific article, which gives lesser importance to the clinical method. We carried out diverse methodical encounters, mainly involving in-depth interviews with the authors of the manuscript and observation in their workplace. The text seeks to recover the histories of work based on the indiciary or semiotic model of knowledge, and recognize the importance of this model in medical practice.

Sobre el carácter indiciario del método clínico: una mirada antropológica a partir de un relato de caso publicado / On the indiciary nature of the clinical method: an anthropological view of a published case study

En este artículo presentamos un relato de caso publicado como objeto de reflexión, sobre el que se realizó una reconstrucción parcial del proceso de estudio y una elaboración diagnóstica del síndrome Uruguay, mostrando las circunstancias del caso, la selección e interpretaciones de "pistas", y algunos de los detalles que fueron relevantes en el raciocinio clínico. Nuestro punto de partida es el reconocimiento del carácter narrativo del conocimiento clínico y del método clínico como un método indiciario. El manuscrito del síndrome Uruguay presenta una estructura narrativa ajustada a las convenciones del artículo científico que pone al método clínico en un segundo plano. Nuestros encuentros metódicos fueron diversos y comprendieron, sobre todo, entrevistas en profundidad a los autores del manuscrito y observaciones en su lugar de trabajo. El texto propone recuperar las historias de trabajo basadas en un modelo de conocimiento indiciario o semiótico y reconocer su importancia en la práctica médica.(AU)

In this article we present a published case study as an object of reflection. On this basis, we carried out a partial reconstruction of the process of study and diagnostic elaboration of the Uruguay syndrome, showing the circumstances of the case, the selection and interpretation of "clues," and some of the details relevant to the clinical reasoning. Our starting point is the recognition of the narrative nature of clinical knowledge and of the clinical method as an indiciary method. The manuscript of the Uruguay syndrome has a narrative structure adjusted to the conventions of a scientific article, which gives lesser importance to the clinical method. We carried out diverse methodical encounters, mainly involving in-depth interviews with the authors of the manuscript and observation in their workplace. The text seeks to recover the histories of work based on the indiciary or semiotic model of knowledge, and recognize the importance of this model in medical practice.(AU)

Sobre el carácter indiciario del método clínico: una mirada antropológica a partir de un relato de caso publicado. / [On the indiciary nature of the clinical method: an anthropological view of a published case study].

In this article we present a published case study as an object of reflection. On this basis, we carried out a partial reconstruction of the process of study and diagnostic elaboration of the Uruguay syndrome, showing the circumstances of the case, the selection and interpretation of "clues," and some of the details relevant to the clinical reasoning. Our starting point is the recognition of the narrative nature of clinical knowledge and of the clinical method as an indiciary method. The manuscript of the Uruguay syndrome has a narrative structure adjusted to the conventions of a scientific article, which gives lesser importance to the clinical method. We carried out diverse methodical encounters, mainly involving in-depth interviews with the authors of the manuscript and observation in their workplace. The text seeks to recover the histories of work based on the indiciary or semiotic model of knowledge, and recognize the importance of this model in medical practice.

Diagnóstico clínico y molecular de síndrome de cefalopolisindactilia de Greig. A propósito de un caso. / Clinical and molecular cephalopolysyndactyly Greig syndrome. A case report

El síndrome de cefalopolisindactilia de Greig (SCPG) es una afección autosómica dominante caracterizada por polidactilia o sindactilia de manos y pies, macrocefalia, hipertelorismo y ocasionalmente anomalías cerebrales y retraso mental. Es un síndrome poco frecuente, heredado según un patrón autosómico dominante. La prevalencia es ignorada, siendo conocidos 100 casos aproximadamente. Más del 75 % de los pacientes con manifestaciones clínicas características de SCPG presentan mutaciones en el gen GLI3. El diagnóstico presuntivo de SCPG puede realizarse cuando el paciente presenta la tríada clásicade polidactilia, hipertelorismo y macrocefalia, siendo indicativo para la realización del análisis molecular del gen GLI3. En este trabajo se describe el caso de un niño referido al Instituto de Genética Médica con diagnóstico clínico de polidactilia y macrocefalia. Las características clínico-evolutivas e imagenológicas del paciente permitieron postular el diagnóstico de SCPG. El análisis molecular del gen GLI3 confirmó el diagnóstico de SCPG identificando la mutación c.1850_1852 del GTTinsAT (p.R617LfsX11) en el exón 12 del gen GLI3. Se trata de una mutación no descrita previamente como una mutación asociada al desarrollo de SCPG; no obstante, al tratarse de una mutación que provoca una proteína truncada desde el exón 12 del gen GLI3, no existen muchas dudas sobre su patogenicidad. Este resultado tiene implicaciones hereditarias y familiares permitiendo un adecuado asesoramiento genético en el contexto familiar.

Limitaciones de los estudios de genética molecular en el proceso diagnóstico de fibrosis quística / Limitations to molecular genetics studies during the cystic fibrosis diagnostic process

Introducción: la fibrosis quística (FQ) es una enfermedad hereditaria autosómica recesiva causada por mutaciones en el gen que codifica una proteína con función de canal de cloruro (CFTR). Se manifiesta como una enfermedad multiorgánica y se caracteriza por una gran heterogeneidad clínica. Existen pacientes que no manifiestan las características clínicas de la forma clásica y se describen como FQ atípica o no clásica. El diagnóstico se basa en unfenotipo clínico consistente más evidencia de disfunción del canal CFTR y/o en la identificación de dos mutaciones causantes de FQ. Ninguna de estas definiciones es suficientepor sí misma para establecer el diagnóstico. Objetivos: mostrar algunas limitaciones de los estudios de genética molecular en el proceso diagnóstico de FQ. Material y método: se consideran cinco casos clínicos de niños referidos con dato clínico de probable FQ y solicitud de estudio genético para la confirmación diagnóstica. Resultados: los estudios realizados no permiten confirmar el diagnóstico de FQ ni descartar un posible diagnóstico de FQ atípica. Conclusiones: la mayoría de las veces el diagnóstico de FQ es claro y los estudios genéticos permiten la confirmación diagnóstica, el asesoramiento genético y eventual diagnóstico prenatal. Sin embargo, el uso y la interpretación de los análisis genéticos presentan diversasdificultades relacionadas con la condición clínico-paraclínica del paciente, las limitaciones técnicas y la elección del conjunto de mutaciones a ser analizadas, especialmente en los casos de FQ atípica. Este trabajo muestra el desafío que puede implicar para el clínico interpretar un resultado molecular e integrarlo en el proceso diagnóstico de FQ.

Introduction: cystic fibrosis is an autosomal recessive hereditary disease caused by mutations of the gene whichencodes a protein with a CFTR chloride channel function. It appears as a multi-organ disease and is characterized bya great clinical heterogeneity. There are patients who do not evidence the classic clinical characteristics and aredescribed as atypical or non-classic cystic fibrosis. Diagnosis is based on a consistent clinical phenotype andevidence of dysfunction in the CFTR channel and/or in the identification of two mutations causing cystic fibrosis.None of these definitions is enough in itself to confirm diagnosis. Objectives: to show a few limitations on the molecular genetic studies in the cystic fibrosis diagnostic process. Method: five clinical cases of children referred withclinical data of probable cystic fibrosis were considered, and they were requested a genetic study to confirm diagnosis. Results: studies conducted do not enable the confirmation of cystic fibrosis diagnosis and neither do theyallow discarding a possible diagnosis of atypical cystic fibrosis. Conclusions: in most cases the diagnosis of cysticfibrosis is clear and genetic studies enable the confirmation of diagnosis, genetic counseling and the final prenataldiagnosis. However, use and interpretation of genetic analysis result in several difficulties regarding the clinical and paraclinical characteristics of patients, technical limitations and choosing the mutations to be analysed, especially in the case of atypical cystic fibrosis. The present study shows the challenge faced by clinicians when interpreting a molecular result to incorporate it into the cystic fibrosis diagnostic process.

Introdução: a fibrose cística FC é uma doença hereditária autossômica recessiva causada por mutações no gene que codifica uma proteína com função nos canais de cloretos CFTR. É uma doença com manifestações múltiplas e se caracteriza por apresentar-se com grande variedade clínica. Alguns pacientes não apresentam as características clínicas clássicas e nesses casos a doença é chamada FC atípica ou não clássica. O diagnóstico é feito através do fenótipo clínico mais consistente associado a evidencia de disfunção do canal CFTR e/ou na identificação de duas mutações causadoras da FC. Nenhuma dessas definições é suficiente para estabelecer o diagnóstico. Objetivos: mostrar algumas limitações dos estudos de genética molecular no diagnóstico de FC.Material e método: são discutidos cinco casos clínicos de crianças referidas com historia clínica de FC provável e pedido de estudo genético para confirmaçãodo diagnóstico. Resultados: os estudos realizados não permitem confirmaro diagnóstico de FC nem descartar um possível diagnóstico de FC atípica.Conclusões: na maioria dos casos o diagnóstico de FC é claro e os estudos genéticos permitem confirmar odiagnóstico, o assessoramento genético e eventual diagnóstico pré-natal. No entanto, o emprego e a interpretaçãodas análises genéticas apresentam varias dificuldades relacionadas com a condição clínica do paciente, aslimitações técnicas e a escolha do conjunto de mutações a ser estudadas, especialmente nos casos de fibrose cística atípica. Este trabalho mostra o desafio que o médico clínico enfrenta para interpretar um resultado molecular e integrá-lo ao processo de diagnóstico de FC.

Clinical, cytogenetic, and molecular characterization of a girl with some clinical features of Down syndrome resulting from a pure partial trisomy 21q22.11-qter due to a de novo intrachromosomal duplication.

We report a girl with a de novo pure partial trisomy 21 with some clinical features of Down syndrome. The girl patient presented a flat broad face, brachycephaly, and a flat nasal bridge. She also had upwardly slanted palpebral fissures, epicanthal folds, blepharitis, brushfield spots, and strabismus. Her mouth was wide with downturned corners, prominent lower lip, narrow and furrowed tongue, and short palate. G-banded chromosomal analysis of metaphases in cells from both skin and blood showed a 46,XX karyotype with additional chromosomal material on the distal short arm of one chromosome 21. Parental chromosomes were normal. Molecular analyses with the short-tandem-repeat (STR) marker D21S2039 (interferon-alpha/beta receptor [IFNAR]) (21q22.1) showed a triallelic pattern. Subtelomeric fluorescent in situ hybridization (FISH) analyses, LSI 13 (retinoblastoma 1 [RB1])/LSI 21(21q22.13-q22.2), and whole chromosome painting probes specific for chromosome 21 showed trisomy for the segment 21q22.13-21q22.2 due to a de novo intrachromosomal duplication. A 500K SNP microarray analysis was then performed and revealed a 13-Mb duplication of 21q22.11-qter. This duplicated material had been translocated onto the end of the "p" arm of one of the chromosome 21s. The karyotype was provisionally defined as 46,XX,add(21)(p12).ish der (21)t(21;21)(p12;q22.11)(WCP21q+,PCP21q++,D215259/D21S341/D21S342++)dn. At the age of 4 years and 10 months, a comprehensive psychological examination was performed and the diagnostic criteria for mental retardation were not fulfilled. In comparison with previously published cases of pure partial trisomy 21, this is a rare finding. Additional studies of such rare patients should aid in the study of the pathogenesis of Down syndrome.

A 14-year follow-up of a case detected prenatally of partial trisomy 13q21.32-qter and monosomy 18q22.3-qter as a result of a maternal complex chromosome rearrangement involving chromosomes 6, 13, and 18.

A balanced complex chromosome rearrangement (CCR) involving three chromosomes is rare and may lead to different types of aneuploid germ cells. We report here a 14-year follow-up of a boy with a karyotype defined as 46,XY,der(18)t(6;13;18)(q21;q21.32;q22.3).ish der(18)(13qter+,18qter-) characterized by multiple congenital abnormalities, including distinctive minor facial anomalies, short neck, abnormalities of the extremities, anogenital abnormalities, flexion contractures, especially at extremities, and severe mental and growth retardation. Chromosome analysis in the mother showed a CCR involving chromosomes 6, 13, and 18. This CCR was the result of a three-break rearrangement, and the derivative chromosome 13 consisted of parts of chromosomes 18 and 13. The karyotype of the child was not balanced, and resulted in partial trisomy for 13q and partial monosomy for 18q detected prenatally by conventional and molecular cytogenetics. Although such a karyotype and its phenotype have not previously been reported, we have compared the clinical and cytogenetic data from our patient with previously described cases of partial trisomy 13q and monosomy 18q despite different break points. We are presenting a new CCR in a woman with normal phenotype with a history of four early abortions and a long follow-up of her malformed newborn with partial 13q trisomy and 18q monosomy.

Síndrome de pterigium múltiple: recurrencia en una familia / Multiple pterygium syndrome: recurrence in a family

En el presente trabajo se describe un caso de síndrome de pterigium múltiple recurrente familiar de particulares características clínicas. Esta descripción se presenta a continuación del artículo “Síndrome de Escobar: a propósito de un caso” para mostrar la heterogeneidad fenotípica y genotípica de esta entidad. El diagnóstico presuntivo se realizó en el primer hijo a los 5 días de vida y el confirmatorio a los dos meses; sobrevivió hasta los 8 meses con desnutrición, ceguera, retraso global del desarrollo y patología renal crónica. Las manifestaciones clínicas incluían fijación generalizada de articulaciones, pterigium de axila, codo y región poplítea, cifosis dorsal, desviación cubital de las manos, pie bot talo-valgo, pabellones auriculares de implantación baja y micrognatia. El diagnóstico presuntivo del segundo hijo fue ecográfico- genealógico, a las 20 semanas de gestación por síndrome de hipoquinesia fetal y fijación articular. El feto obitó a las 21 semanas de edad gestacional. La anatomía- patológica confirmó los hallazgos ecográficos, constatándose un fenotipo muy similar al de su hermano.

A recurrent and familiar case of pterygium multiple syndrome with particular clinical features is presented. This description comes after the article “Escobar syndrome: a case report” in order to show the phenotypic and genotypic heterogeneity of these cases. A preliminary diagnosis was made at 5 days of age in the first child of the couple; the definitive diagnosis was made at 2 months of age. The patient lived 8 months with malnutrition, blindness, developmental delay and chronic renal pathology. Clinical manifestations included joint contractures; elbow, armpit and popliteal region pterygium; dorsal kyphosis; cubital deviation of hands; club foot deformity; low outer ear and micrognathia. The preliminary diagnosis of the second child was ecographic, at 20 weeks of gestation by Hypokinesia fetal and joint contracture. The pregnancy was ended at 21 weeks. The anatomy pathology confirmed the ecographic findings with a phenotype very similar to the first case.

Neoplasia endocrina múltiple tipo 1. Presentación de una familia afectada con diagnóstico molecular / Multiple endocrine neoplasia Type 1. Molecular diagnosis in a family

La neoplasia endocrina múltiple tipo 1 (MEN1) incluye una combinación variable de más de 20 tumores endocrinos y no endocrinos, con herencia mendeliana autosómica dominante. El paciente, con antecedentes familiares de neoplasias, consultó a los 39 años con historia detumor mediastinal y neoplasma de cabeza de páncreas. Se realizó diagnóstico clínico de MEN1 y aceptó ser incluido en un estudio cooperativo conducido por el grupo francés para elestudio de MEN. Se realizó la secuenciación del gene MEN1 detectándose una mutación puntual en el exon 10: 1596delA. Se le informó de la relevancia de realizar el mismo estudioen otros integrantes de la familia en riesgo de presentar igual patología. Dos años después, consultó la hermana de 39 años con historia de hiperparatiroidismo, calciuria, hormonaparatiroidea (PTH) elevada, litiasis renal y operada de adenoma paratiroideo. Refiere que el propósito falleció. Dado el antecedente familiar, se estudió específicamente la mutaciónpreviamente encontrada en el hermano, confirmando el diagnóstico de MEN1. La consultante decidió conocer el estatus molecular de sus dos hijas asintomáticas, no detectándose lamutación en ninguna de ellas. Este trabajo ilustra el beneficio de un diagnóstico que requiere tecnología de alto costo (secuenciación) a través de un estudio colaborativo y que permiteque otros integrantes de la familia puedan conocer su definición molecular. Destacamos la importancia del asesoramiento genético en la toma de decisión de realización del diagnósticomolecular en individuos asintomáticos y la jerarquía del diagnóstico precoz para definir el protocolo de seguimiento en este grupo de pacientes.

Multiple endocrine neoplasia type 1(MEN1) comprises a variable combination of over 20 endocrine and non-endocrine tumors, with Mendelian autosomal dominant inheritance. The patient, who had a family history of tumors, was seen, at age 39, due to a mediastinal tumor and neoplasmat the head of the pancreas. We performed clinical diagnosis of MEN1, and we had the collaboration of aFrench team involved in MEN1 research. We conducted sequenciation of the MEN 1 gene and identified a single mutation in exon 10: 1596delA. The patient was informed about the relevance of performing the same study in othermembers of the family who were likely to carry the same pathology. Two years later, his 39-year-old sister visitedthe clinic, with a history of hyperparathyroidism, calciuria, high parathyroid hormone (PTH), renal lithiasis, and who had undergone parathyroid adenoma surgery. She informed her brother had died. Given the family history, we especially studied the mutation previously found in herbrother, and confirmed the MEN1 diagnosis. Thus, the patient decided to learn about the molecular status in hertwo asymptomatic daughters, whereby no mutations were identified. The present study illustrates the benefit of diagnosis, requiring high cost technology (sequenciation) through a collaborative study, which enables other membersof a family to learn about their molecular definition. We stress the importance of genetic counseling to make a decision regarding the conduction of molecular diagnosisin asymptomatic individuals and the relevance of early diagnosis to define the follow-up protocol for these patients.

A neoplasia endócrina múltipla tipo 1 (MEN1) inclui uma combinação variável de mais de 20 tumores endócrinos enão endócrinos com herança mendeliana autossômica dominante. O paciente, com antecedentes familiares de neoplasmas, consultou aos 39 anos com história de tumor mediastinal e neoplasma de cabeça de pâncreas. Foi realizadoo diagnóstico clínico de MEN1 e o paciente concordou em ser incluído em um estudo cooperativo conduzido por um grupo francês de estudo das MEN. Nasecuenciaçao do gen MEN1 detectou-se uma mutação pontual no éxon 10: 1596delA. O paciente foi informadoda importância de realizar o mesmo estudo em outros integrantes da família com risco de apresentar uma patologia similar. Dois anos depois, sua irmã com 39 anos, consultou apresentando hiperparatiroidismo, calciúria, hormônioparatireóideo (PTH) elevado, litiase renal e operada de um adenoma paratiroideo. A paciente relata o falecimento de seu irmão. Considerando o antecedente familiar, a mutaçãoapresentada pelo irmão foi estudada, o que confirmou o diagnóstico de MEN1. A paciente decidiu estudar o estadomolecular de suas duas filhas assintomáticas, nas quais não se detectou mutação. Este trabalho mostra o beneficio de um diagnóstico que requer tecnologia de alto custo(sequenciação) através de um estudo colaborativo que permite a outros integrantes da família conhecer suadefinição molecular. Destacamos a importância do assessoramentogenético para a tomada de decisão na realização de diagnóstico molecular em indivíduos assintomáticos e a importância do diagnóstico precoce para definir o protocolo de seguimento neste grupo de pacientes.

A 21 years follow-up of a girl patient with a pseudodicentric bisatellited chromosome 22 associated with partial trisomy 22pter-->22q12.1: clinical, cytogenetic and molecular observations.

We present clinical and developmental data on a patient with a de novo recombinant pseudodicentric bisatellited chromosome 22 associated with a partial trisomy 22pter-22q12.1. The patient was evaluated at birth and followed-up until 21 years of age. Clinical findings include facial and digital dysmorphism, hydrocephalus and postnatal-onset growth deficiency. The patient showed bilateral microphthalmia with severe palpebral ptosis and coloboma of the iris and left optic nerve. She also has skeletal and neurological abnormalities, cholesteatoma and seizures. She had absence of speech, poor mobility, poor vision and required help with all daily living skills. Conventional chromosome GTG banded analysis showed that the proband had an abnormal karyotype:46,XX,add(22)(q13). Fluorescence in situ hybridization (FISH) analyses and microsatellite markers for DNA polymorphism study ascertained the karyotype as 46,XX,add(22)(q13.3).ish psu dic(22;22)(q13.3;q12.1)(D14Z1/D22Z1++, N25++, ARSA+, PCP22q+). The recombinant chromosome was stable and present in all cells examined. The paternal origin of the psu dic(22;22) chromosome was determined by using five highly polymorphic microsatellite markers located to the region of chromosome 22q11.2-22q13.33. A 22q13.3 monosomy was ruled out with 22q13.3 cosmid probes covering the terminal 22q-140Kb. The proband carried a recombinant pseudodicentric bisatellited chromosome psu dic(22;22)(q13.3;q12.1). To our knowledge, this is the first report of such rearrangement resulting in partial trisomy 22pter-22q12.1.

Síndrome de trisomía 9p: características clínico-evolutivas y citogenéticas. Seguimiento de doce años / Syndrome of trisomy 9p: clinical and citogenetic characteristics

La trisomía 9p es una anomalía cromosómica que se define por la duplicación parcial o completa del brazo corto de un integrante del par cromosómico 9. Clínicamente se caracteriza por retraso mental y psicomotor, malformaciones craneofaciales distintivas y anomalías de manos y pies. En el presente trabajo describimos el seguimiento clínico durante 12 años de una niña con diagnóstico de trisomía del brazo corto del cromosoma 9, con un cariotipo no balanceado definido por la siguiente fórmula: 46,XX,t(9;21)(q10;q10),+i(9)(p10). Los hallazgos fenotípicos observados en la niña ilustran las deficiencias asociadas con una duplicación completa del brazo corto del cromosoma 9 y ayudan en el asesoramiento genético para esta particular anomalía cromosómica.

Trisomy 9p is a chromosomal anomaly defined by partial or complete duplication of the short arm of one of the members of the 9 pair chromosome. Clinical findings include growth and mental retardation, characteristic craniofacial malformations and hand-foot anomalies. We report a 12 year follow-up of a female patient with trisomy 9p with an unbalanced karyotype defined as: 46,XX,t(9;21)(q10;q10),+i(9)(p10). The observed phenotypic findings illustrate the deficiencies associated with a complete duplication of the short arm of chromosome 9 and can aid in the genetic counseling of this particular chromosomal anomaly.

A fourteen years follow-up of a case of partial trisomy 12q and monosomy 12p recombinants of a familial pericentric inversion of chromosome 12: clinical, cytogenetic and molecular observations.

Partial trisomy 12q and monosomy 12p lead to multiple malformation syndromes. Only four cases were previously reported with the association of these two aneusomies resulting from a familial pericentric inversion of chromosome 12. We report on the clinical, cytogenetic and molecular findings in a boy with an unbalanced karyotype which resulted from a familial pericentric inversion of chromosome 12. The patient was evaluated at birth and followed up until 14 years of age. He showed severe mental retardation, seizures, and dysmorphic features related both to a trisomy 12q and a monosomy 12p. Chromosome breakpoint BAC-FISH mapping revealed that the rec(12) chromosome had a terminal deletion of a 6.7Mb region extending from 12pter to 12p13.31 and a duplicated region of 19.8Mb extending from 12qter to 12q24.13. The findings from the case reported here emphasize the occurrence of some consistent clinical features and illustrate the deficiencies associated with the recombinants from the inversion inv(12)(p13.31q24.13)mat.

A girl with del(4)(q33) and occipital encephalocele: clinical description and molecular genetic characterization of a rare patient.

We present clinical and developmental data on a girl with a de novo terminal deletion of the long arm of chromosome 4, del(4)(q33). The patient was evaluated at birth and followed up until 5 years of age. She showed facial and digital dysmorphism, a complex congenital heart defect, a large occipital encephalocele, and postnatal growth deficiency. Her neuropsychomotor milestones were delayed, and she developed learning difficulties. Apart from standard Giemsa banding, a molecular genetic analysis was performed using a comparative genomic hybridization (CGH) array. This revealed a terminal deletion at the band 4q32.3, which is directly adjacent to 4q33. The clinical findings in our patient differ from those described previously in patients with del(4)(q33) and del(4)(q32), respectively. In particular, the prominent occipital encephalocele has not been observed before in a terminal 4q deletion.

A de novo complex chromosome rearrangement involving chromosomes 2, 3, 5, 9 and 11 detected prenatally and studied postnatally by conventional cytogenetics and molecular cytogenetic analyses.

OBJECTIVE: To describe a de novo complex chromosome rearrangement(CCR) detected prenatally and studied afterbirth. METHODS: Conventional cytogenetics and fluorescent in situ hybridization (FISH) were performed on amniotic fluid and peripheral blood. High-resolution comparative genomic hybridization (HR-CGH) analysis was made postnatally. RESULTS: Prenatal/postnatal cytogenetic, FISH and HR-CGH analyses revealed an apparently balanced de novo CCR ascertained as 46,XY,t(2; 3;9)(q21;p24;q22),der(5)inv(5)(?p11q13)t(5; 11)(?p13;q25),ins(5; 3)(?p13;?p23p24). At 9 months,the child has neither congenital anomalies nor evidence of delayed psychomotor development. CONCLUSIONS: Our report describes a rare CCR detected prenatally and shows the usefulness of FISH and CGH in complementing conventional cytogenetics.

Parental decisions to abort or continue a pregnancy following prenatal diagnosis of chromosomal abnormalities in a setting where termination of pregnancy is not legally available.

OBJECTIVE: To learn about parental decisions to abort or continue a pregnancy after prenatal diagnosis of chromosomal abnormalities among the population in Uruguay. METHODS: Between 1982 and 2003, 14 656 amniocentesis and 2740 chorionic villus samplings were performed in a referral Genetic Unit. Chromosomal anomalies were found in 376 cases (2.16%) and included Down syndrome, aneuploidies in which a severe prognosis was expected, sex chromosome aneuploidy and aneuploidies with a low risk of an abnormal clinical phenotype. The couples that received abnormal results were contacted by phone and asked if they had continued or interrupted the pregnancy after the diagnosis and genetic counseling. RESULTS: We contacted 207 couples (55%). When confronted with Down syndrome or an aneuploidy in which a severe prognosis was expected, 89% and 96% of patients, respectively, decided to terminate the pregnancy. When confronted with sex chromosome aneuploidy or aneuploidies with a low risk of an abnormal clinical phenotype, 79% and 90% of patients, respectively, decided to continue the pregnancy. CONCLUSIONS: The present study shows that when faced with an anomaly such as Down syndrome and aneuploidies in which a severe prognosis was expected, most of the couples decided to terminate the pregnancy, although TOP is not legally available in Uruguay.

Prenatal and postnatal characterization of a de novo Xq22.1 terminal deletion.

We present a case of a de novo Xq22.1 chromosomal terminal deletion discovered prenatally by conventional cytogenetics. The pregnancy resulted in the birth of a normal girl. Preferential inactivation of the abnormal X was demonstrated postnatally. Fluorescence in situ hybridization (FISH) demonstrated a terminal Xq deletion spanning Xq22.1 -->qter. An X painting probe ruled out a translocation. The deleted X chromosome was determined to be of paternal origin. The girl is now 4 years old with normal physical and psychomotor development. X chromosomal deletions are infrequent findings in prenatal diagnosis and present a difficult counseling challenge when they occur. Prenatal X-inactivation studies provide an opportunity for more informative genetic counseling when a de novo X chromosome deletion is detected.