Human Genetics of Hypoplastic Left Heart Syndrome.

Hypoplastic left heart syndrome (HLHS) is a severe congenital cardiovascular malformation characterized by hypoplasia of the left ventricle, aorta, and other structures on the left side of the heart. The pathologic definition includes atresia or stenosis of both the aortic and mitral valves. Despite considerable progress in clinical and surgical management of HLHS, mortality and morbidity remain concerns. One barrier to progress in HLHS management is poor understanding of its cause. Several lines of evidence point to genetic origins of HLHS. First, some HLHS cases have been associated with cytogenetic abnormalities (e.g., Turner syndrome). Second, studies of family clustering of HLHS and related cardiovascular malformations have determined HLHS is heritable. Third, genomic regions that encode genes influencing the inheritance of HLHS have been identified. Taken together, these diverse studies provide strong evidence for genetic origins of HLHS and related cardiac phenotypes. However, using simple Mendelian inheritance models, identification of single genetic variants that "cause" HLHS has remained elusive, and in most cases, the genetic cause remains unknown. These results suggest that HLHS inheritance is complex rather than simple. The implication of this conclusion is that researchers must move beyond the expectation that a single disease-causing variant can be found. Utilization of complex models to analyze high-throughput genetic data requires careful consideration of study design.

Epigenetics.

Epigenetics is the study of heritable changes to the genome and gene expression patterns that are not caused by direct changes to the DNA sequence. Examples of these changes include posttranslational modifications to DNA-bound histone proteins, DNA methylation, and remodeling of nuclear architecture. Collectively, epigenetic changes provide a layer of regulation that affects transcriptional activity of genes while leaving DNA sequences unaltered. Sequence variants or mutations affecting enzymes responsible for modifying or sensing epigenetic marks have been identified in patients with congenital heart disease (CHD), and small-molecule inhibitors of epigenetic complexes have shown promise as therapies for adult heart diseases. Additionally, transgenic mice harboring mutations or deletions of genes encoding epigenetic enzymes recapitulate aspects of human cardiac disease. Taken together, these findings suggest that the evolving field of epigenetics will inform our understanding of congenital and adult cardiac disease and offer new therapeutic opportunities.

Human Genetics of Ventricular Septal Defect.

Ventricular septal defects (VSDs) are recognized as one of the commonest congenital heart diseases (CHD), accounting for up to 40% of all cardiac malformations, and occur as isolated CHDs as well as together with other cardiac and extracardiac congenital malformations in individual patients and families. The genetic etiology of VSD is complex and extraordinarily heterogeneous. Chromosomal abnormalities such as aneuploidy and structural variations as well as rare point mutations in various genes have been reported to be associated with this cardiac defect. This includes both well-defined syndromes with known genetic cause (e.g., DiGeorge syndrome and Holt-Oram syndrome) and so far undefined syndromic forms characterized by unspecific symptoms. Mutations in genes encoding cardiac transcription factors (e.g., NKX2-5 and GATA4) and signaling molecules (e.g., CFC1) have been most frequently found in VSD cases. Moreover, new high-resolution methods such as comparative genomic hybridization enabled the discovery of a high number of different copy number variations, leading to gain or loss of chromosomal regions often containing multiple genes, in patients with VSD. In this chapter, we will describe the broad genetic heterogeneity observed in VSD patients considering recent advances in this field.

Detection of 4p16.3 deletion and 11p15.5p15.4 gain in a boy by comparative genomic hybridization array: A case report.

BACKGROUND: Nonallelic homologous recombination (NAHR) of segmental duplications or low copy repeats (LCRs) result in DNA gain/loss and play an important role in the origin of genomic disorders. CASE SUMMARY: A 3-year- old boy was referred for genetic analysis. Comparative genomic hybridization array analysis revealed a loss of 3776 kb in the 4p16.3 chromosomal region and a gain of 3201 kb in the 11p15.5p15.4 chromosomal region. CONCLUSION: Genomic imbalances caused by NAHR in LCRs result in deletion and duplication syndromes.

Wolf-Hirschhorn Syndrome with Hyperparathyroidism: A Case Report and a Narrative Review of the Literature.

Wolf-Hirschhorn syndrome (WHS) is a contiguous gene deletion condition. The WHS core phenotype includes developmental delays, intellectual disabilities, seizures, and distinctive facial features. Various other comorbidities have also been reported, such as hearing loss, heart defects, as well as eye problems and kidney problems. In this report, we present a case of WHS accompanied by hyperparathyroidism and hypercalcemia, which has not been previously reported. A girl was born at 37 weeks of gestation by vaginal delivery. She was small for the gestational age (2,045 g) and admitted to neonatal intensive care unit. She had typical WHS facial features and was found to have bilateral small kidneys associated with transient metabolic acidosis and renal insufficiency. She had right-sided sensorineural hearing loss, a small atrial septal defect, and colpocephaly and hypoplasia of corpus callosum. She had a single seizure which was well controlled with an oral antiepileptic medication. Cytogenetic studies demonstrated a large terminal chromosome 4p deletion (21.4 Mb) and 4p duplication (2.1 Mb) adjacent to the deletion. A unique finding in this patient is her consistently elevated levels of parathyroid hormone and serum calcium, suggesting hyperparathyroidism. We present this rare case along with a review of the literature and hope to draw an attention to a potential relationship between WHS and hyperparathyroidism.

Síndrome de Wolf-Hirschhorn: Descripción de cinco casos caracterizados por microarrays de polimorfismos de nucleótido único / Wolf-Hirschhorn syndrome: Description of five cases characterized by means of single nucleotide polymorphism microarrays

El síndrome de Wolf-Hirschhorn es una entidad polimalformativa debida a la microdeleción en la región distal del brazo corto del cromosoma 4 (4p16.3), el cual produce una serie de manifestaciones clínicas, que pueden variar dependiendo del tipo y tamaño del defecto genético en este síndrome de genes contiguos. Se presentan cinco pacientes, tres de ellos de sexo femenino, todos con los hallazgos clínicos primordiales, con rasgo facial característico de "apariencia en casco de guerrero griego", retraso en el crecimiento y del desarrollo psicomotor. Además de la deleción parcial en la región distal del brazo corto del cromosoma 4, en dos pacientes, se encontraron alteraciones genéticas adicionales, mediante el uso de microarrays de polimorfismos de nucleótido único. Se resaltan las características clínicas del síndrome de Wolf-Hirschhorn con la finalidad de orientar el diagnóstico, brindar una atención médica interdisciplinaria y, a través de su confirmación, brindar un adecuado asesoramiento genético familiar.

Wolf-Hirschhorn syndrome is a polymalformative entity due to the microdeletion in the distal region of the short arm of chromosome 4 (4p16.3), which produces a series of clinical manifestations that can vary depending on the type and size of the genetic defect in this contiguous gene syndrome. Five patients are presented, three of them female, all with the primary clinical findings, characterized by "Greek warrior helmet appearance" facial feature, growth retardation and psychomotor development delay. In addition to the partial deletion in the distal region of the short arm of chromosome 4, two additional genetic alterations were found in two patients, through the use of single nucleotide polymorphism arrays. The clinical characteristics of Wolf-Hirschhorn syndrome are highlighted in order to guide the diagnosis, provide interdisciplinary medical care and, through its confirmation, provide adequate family genetic counseling.

Crecimiento intrauterino restringido como síntoma guía para el diagnóstico genético prenatal del síndrome de Wolf-Hirschhorn en gestación gemelar bicorial biamniótica / Restricted Intrauterine Growth as a Guiding Symptom for Prenatal Genetic Diagnosis of Wolf-Hirschhorn Syndrome in Bicorial Diamniotic Twin Gestation

El síndrome de Wolf Hirschhorn, también conocido como monosomía del brazo corto del cromosoma 4 (4p) o síndrome 4p-, es una rara enfermedad genética descrita por primera vez en el año 1961 por los doctores Cooper y Hirschhorn. El objetivo del trabajo es presentar un caso clínico sobre el síndrome de Wolf-Hirschhorn, que es un trastorno genético raro y aún bastante desconocido que cursa con múltiples anomalías morfológicas congénitas, así como con un retraso neurológico e intelectual de grado variable. La prevalencia de este síndrome es extremadamente baja, teniendo en cuenta que la cifra puede estar infraestimada, dada las pérdidas gestacionales precoces y la dificultad en el diagnóstico prenatal. Reportamos el caso de una paciente con gestación gemelar bicorial biamniótica tras un ciclo de FIV-ICSI, en el que al segundo gemelo se diagnosticó un Síndrome de Wolf-Hirschhorn, luego del estudio por una discordancia de pesos estimados y crecimiento intrauterino restringido de este segundo feto. El patrón clásico de presentación clínica se caracteriza por el desarrollo de alteraciones craneofaciales importantes, retraso en el crecimiento normal tanto prenatal como posnatal y deficiencia mental e intelectual de grado variable. El diagnóstico prenatal debe ser realizado por expertos. Puede sospecharse por un crecimiento intrauterino restringido, ya que se da en 80-90 por ciento de los fetos con esta patología. Una vez diagnosticado, se recomienda el estudio genético de los padres, dado que hasta 15 por ciento de los progenitores pueden padecer un reordenamiento cromosómico equilibrado en el brazo corto del cromosoma 4(AU)

Wolf Hirschhorn syndrome, also known as monosomy of the short arm of chromosome 4 (4p) or 4p-syndrome, is a rare genetic disorder first described in 1961 by doctors Cooper and Hirschhorn. The prevalence of this syndrome is extremely low, taking into account that the figure may be underestimated given the early gestational losses and the difficulty in prenatal diagnosis. The objective of the study is to present a clinical case of Wolf-Hirschhorn syndrome, presenting with multiple congenital morphological anomalies, as well as a neurological and intellectual retardation of variable degree. We report the case of a patient with a bicorial biamniotic twin gestation after a cycle of IVF-ICSI. The second twin was diagnosed with a Wolf-Hirschhorn syndrome, after performing the corresponding study due to a discordance of estimated weights and restricted intrauterine growth of this second fetus. The development of important craniofacial alterations, delay of normal prenatal and postnatal growth, and mental and intellectual deficiency of variable degree characterize the classic clinical presentation. Experts must make prenatal diagnosis. Wolf-Hirschhorn syndrome can be suspected by a restricted intrauterine growth, as it occurs in 80-90 percent of fetuses with this pathology. Once diagnosed, the genetic study of the parents is recommended, since up to 15 percent of the parents can suffer a balanced chromosomal rearrangement in the short arm of chromosome 4(AU)

Uncommon Oral Cleft in Wolf-Hirschhorn Syndrome

Wolf-Hirschhorn syndrome (WHS) is a syndrome with craniofacial and systemic abnormalities, which is related to 4p deletion. A 3-month old girl with an undiagnosed syndrome was referred for evaluation of the cleft lip and palate. Hypotonia, short stature, cardiac malformation, hypertrophied clitoris, and atypical thumb of both hands was observed. Microcephaly, low-set ear, prominent glabella, downslanting palpebral fissures, a characteristic "Greek warrior helmet" appearance, micrognathia, ears with pits/tags and bilateral incomplete cleft lip apart from incomplete cleft palate were observed as craniofacial findings. With clinical diagnosis of WHS, blood was subjected to karyotyping, which showed a 4p15.2 deletion, consistent with the condition. Here is reported the case of this WHS patient with an uncommon oral cleft extending the phenotypic spectrum of the disorder. The child was referred to a multidisciplinary team to reparative surgery of the cleft lip and palate. The patient is on regular medical follow-up and will be further assisted by dentists, physical therapists, occupational therapists and psychologists. The genotype-phenotype correlation of the affected patient with previous WSH syndrome reports is described.

A síndrome de Wolf-Hirschhorn (WHS) é uma condição genética caracterizada por anomalias craniofaciais e sistêmicas, causada por deleção cromossômica na região 4p. Paciente de 3 meses de idade, gênero feminino, foi encaminhada para avaliação de fissura de lábio e fissura palatina, associada a uma síndrome não diagnosticada. A paciente apresentava-se com hipotonia, baixa estatura, malformação cardíaca, clitóris hipertrofiado e implantação atípica do polegar nas duas mãos. Microcefalia, baixa implantação da orelha, glabela proeminente, inclinação baixa das fissuras palpebrais, aparência característica de capacete de guerreiro grego, micrognatia, fossetas em orelhas, fissura labial bilateral incompleta e fissura palatina incompleta foram observadas como características craniofaciais. Com um diagnóstico clínico de WHS, foi realizado o cariótipo, que mostrou a deleção 4p15.2, consistente com a condição. Esse relato de caso apresenta um caso de WHS, com uma fissura oral incomum, ampliando o espectro fenotípico da doença. A paciente foi encaminhada a tratamento com equipe multidisciplinar para correção cirúrgica da fissura labial e palatina. Encontra-se em acompanhamento médico bem como odontológico, fisioterapêutico e em terapia ocupacional e psicológica. Uma correlação entre genótipo e fenótipo pode ser observada nesse relato da síndrome de WHS.

Síndrome de Wolf-Hirschhorn: reporte de un caso clínico y revisión de la literatura / Wolf-Hirschhorn syndrome: case report and literature review

El síndrome de Wolf-Hirschhorn es un trastorno cromosómico atribuible a una delección parcial del brazo corto del cromosoma 4 (4p-). Está caracterizado por hallazgos craneofaciales típicos en la infancia (“apariencia de guerrero griego” de la nariz, microcefalia, frente alta con glabela prominente, hipertelorismo, cejas muy arqueadas, filtrum corto, boca en carpa, y micrognatia, entre otros), retardo del crecimiento pre y postnatal, hipotonía y retardo del desarrollo. Los pacientes también pueden tener epilepsia y anormalidades que involucran otros órganos. El diagnóstico puede ser realizado por análisis citogenético convencional, el cual detecta la mayoría de los casos. El tratamiento incluye rehabilitación, terapia de lenguaje, drogas antiepilépticas cuando son necesarias, alimentación por gavaje o gastrostomía para las dificultades de la alimentación y terapia de soporte. Femenina de 10 meses de edad, quien presenta anomalías craneofaciales características, pie equinovaro bilateral, hipotonía, reflujo gastroesofágico, epilepsia, retardo del crecimiento y del desarrollo. El diagnóstico fue confirmado por detección de una delección de 4p que involucraba a la región crítica para este síndrome. Esta paciente recibe actualmente rehabilitación, medicación antirreflujo y ácido valproico. Esta condición debe ser reconocida por los pediatras, a fin de poder ofrecer un adecuado manejo a estos pacientes y sus familias.

Wolf-Hirschhorn Syndrome is a cromosomal disorder attributable to partial deletion of the short arm of chromosome 4(4p-). It is characterized by typical craneofacial features in infancy (“Greek warrior appearance” of the nose, microcephaly, high forehead with prominent glabella, hypertelorism, highly arched eyebrows, short philtrum, downturned mouth and micrognathia, among others), pre and postnatal growth retardation, hypotonia and developmental delay. Patients can also have epilepsy and abnormalities that involve other organs. Diagnosis can be made by conventional cytogenetic analysis which detects most of the cases. Treatment includes rehabilitation, speech therapy, antiepileptic drugs when necessary, gavage feeding or gastrostomy for feeding difficulties and standard management of other anomalies. 10 month-old female who presents characteristic craniofacial anomalies, clubfeet, hypotonia, gastroesofageal reflux, epilepsy, growth retardation and developmental delay. Diagnosis was confirmed by detection of a deletion of 4p that involved the critical region of the syndrome. This patient receives rehabilitation, antireflux medication and valproic acid. This condition must be recognized by pediatricians in order to offer adecuated management to these patients and their families.

Síndrome de Wolf-Hirschhorn (deleção do braço curto do cromossomo 4p): Relato de caso / Wolf-hirschhorn syndrome (terminal deletion of the short arm of chromosome 4p): case report

Objective: to report a case of Wolf-Hirschhorn Syndrome or partial deletion of the short arm of one chromosome 4 and present a brief literature review. Case Report: the authors report a case of a seven years-old child presenting the main findings of the syndrome: hypertelorism, big and large nose, prominent glabella, high arched eyebrows, antimongoloid palpebral fissures, bilateral low implantation of auricles, and microcephaly. Echodopplercardiographic study evidenced interatrial communication type ostium secundum without hemodynamic repercussion. Radiological examination showed clubfeet. The patient presents many cognitive deficits, mainly in functions as interaction and learning. Evident motor dysfunctions compromising gait and also muscle atrophy. The child also presented convulsive crises in the first year of life that are currently controlled by the use of anticonvulsants. Final considerations: the incidence of the Wolf-Hirschhorn Syndrome is rare, with only 100 cases reported until1981. The prognosis is relative, with one third of the patients dying with in the first year, while other children are alive with more than twelve years of age. This case was diagnosed based on clinical, radiological, echodopplercardiographical criteria and confirmed by the karyotype's result 46,XX,del(4)(p15?1).

Objetivo: descrever um caso de síndrome de Wolf-Hirschhorn ou deleção parcial terminal do braço curto de um dos cromossomos 4 e apresentar uma breve revisão da literatura. Relato de Caso: criança de sete anos que apresenta os principais aspectos da síndrome: hipertelorismo, nariz grande e adunco, glabela proeminente, fissuras palpebrais antimongolóides, implantação baixa dos pavilhões auriculares, micrognatia e microcefalia. Radiografias do esqueleto revelaram má formação óssea, causando pés eqüinovaros. A ecodopplercardiografia evidenciou CIA sem repercussão hemodinâmica. A paciente apresenta inúmeros déficits cognitivos, fundamentalmente nas funções de interação e aprendizado, além dos distúrbios motores evidentes, com comprometimento da marcha e atrofia muscular; crises convulsivas no primeiro ano de vida, mas que estão atualmente controladas pelo uso de anticonvulsivante. Considerações Finais: a incidência da Síndrome de Wolh-Hirschhorn é rara, com 100 casos publicados até 1981. O prognóstico é relativo, com 1/3 dos pacientes morrendo no decorrer do primeiro ano, enquanto outras crianças estão vivas com mais de 12 anos. O caso apresentado foi diagnosticado com base em critérios clínicos, radiológicos, ecodopplercardiogáficos e confirmado pelo resultado do cariótipo: 46,XX,del(4)(p15?1).

Influência do tratamento intradisciplinar no desenvolvimento motor na síndrome de wolf-hirschhorn: estudo de caso / Influence of the intradisciplinary team on the motor development in wolf-hirschhorn syndrome: case study

A Síndrome de Wolf-Hirschhorn (SWH) é uma desordem genética incomum, com incidência de 1:50.000 nascidos vivos, descrita pela primeira vez por Hirschhorn, Cooper e Firschein, em 1961. Resulta da microdeleção distal do braço curto do cromossomo 4, mais especificamente em 4p16.3. A condição é normalmente associada com complexa expressão fenotípica que inclui malformações múltiplas com características crânio-facial típicas, e é caracterizada por atraso no desenvolvimento neuropsicomotor (DNPM), retardo mental e de crescimento, microcefalia, hipotonia muscular congênita, crises convulsivas, cardiopatias cong6nitas e anomalias renais, esqueléticas e oftálmicas. Esta pesquisa constitui-se no estudo de um caso relativo a uma criança com a SWH, seis anos e nove meses de idade, sexo masculino, que apresenta, além das características fenotípicas, atraso no DNPM, com a finalidade de verificar a influência da atuação da equipe intra-disciplinar no seu crescimento e desenvolvimento. Para a avaliação do paciente utilizou-se o Teste de Desenvolvimento de Denver, no qual apresentou desenvolvimento m6dio compatível com a idade de seis meses, e o Cartão de Desenvolvimento Neurológico, que também evidenciou atraso no DNPM. A atuação intra-disciplinar - participação conjunta de médicos, fisioterapeuta, terapeuta ocupacional e fonoaudiólogo - trouxe benefícios significativos, visto que a evolução do paciente foi superior a esperada em relação aos relatos da literatura.

The Wolf-Hirschhorn Syndrome (WHS) is an unusual genetic disorder with an incidence of 1 in 50,000 births. It was first described by Hirschhorn, Cooper and Firschein in 1961, and it results from the deletion of the distal short arm of chromosome 4, more specifically 4p 16.3. This condition is normally associated with a complex phenotypic expression that includes multiple malformations with typical cranio¬facial features. It is characterized by delayed neuropsychomotor development (NPMD), severe mental and growth retardation, microcephaly, congenital muscular hypotonia, seizures, congenital heart defect, ophthalmic, skeletal and renal disorders. This paper is a case study involving a male child aged six years and eleven months old, with WHS, presenting all the phenotypic features and NPMD retardation as well. The research intended to verify the influence of the intradisciplinary team on the growth and development of this child. Patient was evaluated with Denver Test of Development, in which presented an average development compatible with a 6-month-old child, and the Neurological Development Card, which resulted in NPMD retardation as well. The actuation of the intradisciplinary team - including physicians. physiotherapists, occupational therapists and speech therapists - has presented very beneficial results, since the patient's evolution was much superior than the expected considering literature reports.