Cornelia De Lange syndrome

O que é Cornelia De Lange syndrome?

Cornelia De Lange syndromeé uma doença genética com um fenótipo amplamente variado. Isso significa sintomas variam significativamente entre os indivíduos, tanto em termos de apresentação quanto de gravidade. A maioria dos pacientes compartilha algumas características faciais, bem como baixa estatura e / ou anormalidade de crescimento.

O síndromes também é conhecido como Brachman De Lange, CDLS ou De Lange síndromes.

Síndromes Sinônimos:
BDLS Brachmann-de Lange síndromes CDLS Cornelia De Lange syndrome Typus degenerativus Amstelodamensis

O que a mudança genética causa Cornelia De Lange syndrome?

Cornelia De Lange syndromeocorre em 60% dos casos quando há uma mutação no gene NIPBL. Em apenas 10% dos casos, a mutação ocorre nos genes SMC1A, SMC3, HDAC8 ou RAD21. 30% dos casos têm uma causa desconhecida.

Em alguns casos, uma genética síndromes pode ser o resultado de uma mutação de novo e o primeiro caso em uma família. Neste caso, trata-se de uma nova mutação gênica que ocorre durante o processo reprodutivo.

Quais são os principais sintomas de Cornelia De Lange syndrome?

O principal sintomas de Cornelia De Lange syndrome pode variar entre os indivíduos e também pode variar na extensão de sua gravidade.

Características faciais típicas do síndromes incluem uma ponte nasal côncava, nariz pequeno, sobrancelhas grossas e longas, lábio superior fino e boca descendente. A baixa estatura também é típica do síndromes.

Outros possiveis sintomas pode incluir crescimento e atraso no desenvolvimento. Deficiência intelectual e deficiências relacionadas especialmente ao comportamento e às condições sociais. As tendências autistas são comuns para alguns indivíduos.

Outras condições de saúde podem incluir anomalias esqueléticas, defeitos cardíacos congênitos, problemas gastrointestinais, convulsões, fenda palatina e crescimento excessivo de pelos. Anormalidades genitais, miopia e perda auditiva e falta de dedos nas mãos e nos pés também podem se apresentar como sintomas.

Possíveis traços / características clínicas:
Colocação proximal do polegar, Sinofrio, Mão pequena, Baixa estatura, Pé curto, Refluxo gastroesofágico, Palato alto, Ponte nasal proeminente, Sobrancelha altamente arqueada, Hirsutismo, Atraso de desenvolvimento global, Clinodactilia do 5 dedo, Dificuldades de alimentação na infância, Borda vermelha fina, movimento limitado do cotovelo, miopia, deficiência intelectual, cílios longos

Como alguém faz o teste de Cornelia De Lange syndrome?

O teste inicial para Cornelia De Lange syndrome pode começar com a triagem de análise facial, por meio do FDNA Telehealth plataforma telegenética, que pode identificar os principais marcadores do síndromes e delineia a necessidade de mais testes. Seguirá uma consulta com um conselheiro genético e, em seguida, um geneticista. 

Com base nesta consulta clínica com um geneticista, as diferentes opções para testes genéticos serão compartilhadas e o consentimento será solicitado para testes adicionais.

Informações médicas sobre Cornelia De Lange syndrome

Cornelia De Lange syndromeis characterized by distinctive facial features (synophrys, highly arched eyebrows, long eyelashes, short nose with anteverted nares, microcephaly), short stature, hirsutism, and upper limb reduction defects. Cornelia De Lange syndrome 1 is the most common subtype of Cornelia De Lange syndrome, featuring a variable presentation that can range from mild to severe. Cornelia De Lange syndrome 1 is caused by heterozygous mutations in the NIPBL gene on chromosome 5p13.2.

This intellectual disability syndrome is characterized clinically by low birth-weight in the majority, short stature, microcephaly, and generalised hirsutism resulting in synophrys, a hairy forehead, hairy ears and marked hair whorls on the posterior trunk and arms. The nose is short, the nostrils anteverted and flared, and there is a long philtrum and a thin upper lip with a midline beak. Feeding difficulties (Luzzani et al., 2003), irritability, a deep hoarse cry, and increased tone in the limbs are common early problems. Upper limb defects are common and vary from proximally placed thumbs to absence deformities and ectrodactyly (Braddock et al., 1993, Barboni et al., 2012). The orthopaedic features are well reviewed by Roposch et al., (2004). Three cases with cervical spine (fusion, insatbility, odontoid malformation) were reported by Bettini et al., (2014). Thrombocytopenia may also be a rare finding (Froster and Gortner, 1993; Fryns and Vinken, 1994, Lambert et al., 2011). Ozkinay et al., (1998) reported a case with vermis hypoplasia. Hayashi et al., (1996) reported a case with septo-optic dysplasia and cerebellar hypoplasia. Florez et al., (2002) reported a case with keratosis pilaris atrophicans faciei (ulerythema ophryogenes). Extensive reviews of the condition are to be found in the reports of papers from the 12th Annual David W. Smith Workshop (Graham, 1993). About 33% have cardiac malformations (Selicorni et al., 2009).
Kliewer et al., (1993) provide valuable data on fetal growth derived from ultrasound studies. Limb defects might be picked up in utero, and in addition diaphragmatic hernia appears to be relatively common (Cunniff
et al., 1993; Marino et al., 2002). Aitken et al., (1999) presented data suggesting that levels of plasma protein-A levels are reduced in mothers carrying fetuses with de Lange syndrome in the second trimester.
The phenotype is variable but the condition should be diagnosed with extreme caution in those who are not mentally handicapped. The existence of a milder form of the condition, sometimes with autosomal dominant inheritance, is still controversial. de Die-Smulders et al., (1992) reported a moderately retarded boy with the condition whose mother had normal intelligence, but had convincing facial features of the condition. de Die-Smulders et al., (1994) suggested that transmission of mild de Lange syndrome was exclusively maternal. However, Chodirker and Chudley (1994) reported a convincingly affected father and son. Mckenney et al., (1996) reported convincingly affected half sibs with a common father. McConnell et al., (2003) reported a convincingly affected mother and daughter. Less convincing was their suggestion that the father was affected. Other 'dominant' cases cited from the literature are less convincing (eg: Bankier et al., 1986; Kumar et al., 1985; Leavitt et al., 1985; Kozma 1996). Russell et al., (2001) reported another father and daughter with apparent dominant inheritance, and provide a good review of reports of dominant inheritance in the literature. Borck et al., (2006) reported a father daughter pair, both with a NIPBL gene mutation.
Baraitser and Papavasiliou (1993) reported MZ twins who possibly had the mild form of the condition. Further cases with mild features, and valuable discussion of this phenotype can be found in Bay et al., (1993), Moeschler and Graham (1993), Clericuzio (1993), Saal et al., (1993) and Saul et al., (1993). Zankl et al., (2003) reported a convincing case with limb asymmetry and pigmentary abnormalities, suggesting mosaicism. Allanson et al., (1997) discuss the use of facial measurements to diagnose both the classical and mild forms. In some mild cases, only sequencing will solve the problem (Hansen et al., 2013)
Bhuiyan et al., (2006) described shortening of one or more metatarsal bones in a large group of patients. The patients were psychologically tested, and a form of autism, specific for Cornelia De Lange syndrome was described.
Concordance in monozygotic twins and affected sibs with the classic form have occasionally been reported (see Fryns et al., 1987 and Krajewska-Walasek et al., 1995) but most cases are sporadic. Carakushansky et al., (1996) reported discordant DNA fingerprint-proven monozygotic female twins. Ireland et al., (1991) reported a convincing case with a 3q26:17q23 de novo translocation. Children with duplication of 3q also show some features of de Lange syndrome. Holder et al., (1994) reported two children with features of mild de Lange syndrome and a distal duplication of 3q25.1-26.2 as a result of an unbalanced translocation involving chromosomes 3 and 10. Ireland et al., (1995) showed that the duplicated band was in fact 3q26.3, which was also involved in their translocation case (Ireland et al., 1991). However, Shaffer et al., (1993) failed to find evidence of uniparental disomy for chromosome 3 in sixteen cases of de Lange syndrome, nor Marchi et al., (1994) in 26 cases.
Melegh et al., (1996) reported a case with multiple mitochondrial DNA deletions and persistent hyperthermia, however no clinical photographs were published.
The condition has been characterized molecularly: Krantz et al., (2004) and Tonkin et al., (2004) published mutations in the NIPBL gene (at 5p13-p14). This is the human homolog of the fruit fly Nipped-B gene, that plays a role in Notch-signalling. In a further study of 120 patients, Gillis et al., (2004) found mutations in 47% and the figure in the Borck et al., (2004) cohort of patients was 37%. Miyake et al., (2005) found 4 mutations in 15 Japanese patients. Price et al (2005) reported a case with a balanced 3;5 translocation. Yan et al., (2006) found mutations in 46%, Bhuiyan et al., (2006) 56% of patients. Usually patients with a truncating mutation had a more severe phenotype, as scored in a severity score, but there were exceptions. There was no correlation between the behaviour and the type of mutation. Two affected sibs were reported by Niu et al., (2006). A NIPBL mutation was found in 1 of the sibs (the other had died), and in the unaffected father's sperm. He was a gonadal mosaic. Gonadal mosaicism was reported by Slavin et al., (2012) in 12 families with recurrences. In general (Pie et al., 2010), those with NIPBL mutations have a more severe phenotype. NIPBL interacts with MAU2 to initiate loading of cohesin unto chromatin (Braunholz et al., 2012).
Baynam et al., (2008) reported a case with an 8p23 deletion that clinically resembled Cornelia De Lange syndrome with a diaphragmatic hernia. TANKYRASE 1 gene might be involved.
Somatic mosaicism with linear pigmentation/depigmentation occurred but no limb defects (Castronovo et al., 2010). Using buckle smears in mutation negative cases, Huisman et al., (2013) found a high incidence of mosaicism. It might be necessary (Baquero-Monyoya et al., (2014) to resort toa gene panel enriched sequencing analysis.
In a study by Ansari et al., (2014) of a large cohort of patients with de lange or de lange-like phenotypes, 28% had NIPBL mutations, 3% SMC1A mutations, 3% SMC3 and 3.6% HDAC8. Further cases with SMC3 mytations were reported by Gil-Rodriguez et al., (2015). The phenotype had less distinctive facial features, postnatal microcephaly, a milder prenatal growth retardation, few heart defects and limb malformations. Mutations in TAF1 have also been implicated (Yuan et al., 2015).
Kayembe Kitenge et al., (2016) reported a child with dysmorphic features suggestive of Cornelia De Lange syndrome and grade 3 microtia of the right ear; the left ear was normal.
Nizon et al., (2016) reported on a series of 38 patients with Cornelia De Lange syndrome with heterozygous NIPBL mutations. In three patients, mutations could be detected in buccal cells only due to the presence of somatic mosaicism. The authors recommended performing buccal cell DNA analysis instead of blood DNA analysis to all patients with suspected NIPBL mutations.
Pozojevic et al., (2017) described two unrelated patients with mutations in mosaic state in the NIPBL gene. In both patients, mutations were confirmed in fibroblasts and oral mucosa but could not be detected in blood.
Ayerza Casas et al., (2017) reviewed the incidence of congenital heart disease in a cohort of 149 patients with Cornelia De Lange syndrome. In this cohort, 34.9% of patients had congenital heart disease. The most frequent diagnoses were pulmonary stenosis (15.4%), interauricular septal defect (13.5%), ventricular septal defect (11.5%), patent ductus arteriosus (9.6%), and hypertrophic cardiomyopathy (5.8%). All patients with SMC3 mutations had congenital heart disease; cardiac abnormalities were found in 60% of patients with HDAC8 mutations, 33% of NIPBL mutations, and 28.5% of SMC1A mutations.
Boyle et al., (2017) described a familial case of Cornelia De Lange syndrome. Both the proband and her mother had microcephaly, learning difficulties, and classical facial features, which were more apparent in the daughter. The aunts had low anterior and posterior hairline, short and broad neck, bilateral limited elbow extension, and hearing loss. One of the aunts had cleft palate and mild structural heart disease. Another aunt was diagnosed with osteoporosis. The authors identified a novel c.704delG frameshift RAD21 gene mutation in this family.

* This information is courtesy of the L M D.
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