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Costello syndrome (CSTLO)
O que é costello síndromes?
Costello síndromes é uma doença genética rara que se acredita afetar apenas 200-300 pessoas em todo o mundo, até o momento.
Indivíduos com o síndromes estão em maior risco de tumores não cancerosos e cancerosos, incluindo papiloma e uma forma de câncer infantil conhecida como rabdomiossarcoma.
Uma fácies grosseira característica, assim como verrugas faciais são constantes nesta doença rara. Assim como a pele solta em diferentes partes do corpo.
Faciocutaneoesquelético Síndromes; Fcs Síndromes
Que mudança genética causa em Costello síndromes?
Mutações espontâneas no gene HRAS causam a maioria dos casos de síndromes de Costello.
A síndrome não é hereditária. Embora tenha sido sugerido que a herança autossômica recessiva, autossômica dominante com mutações somáticas também são responsáveis.
Em alguns casos, uma síndrome genética 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 Costello síndromes?
O principal sintomas do síndromes são o atraso no desenvolvimento e a deficiência intelectual.
Falta de crescimento, baixa estatura e defeitos cardíacos congênitos também são características da doença.
Características físicas do síndromes incluem distintas dobras soltas na pele das mãos e pés, especialmente, boca grande, lábios grossos, baixa estatura, anormalidades esqueléticas, problemas dentários e problemas de visão. Hipotonia ou baixo tônus muscular também são comuns.
Possíveis traços / características clínicas:
Supercrescimento, Pectus carinatum, Herança autossômica dominante, Fontanela anterior larga, Prega cutânea nucal espessada, Insuficiência renal, Pescoço alado, Pescoço curto, Sucção insuficiente, Pneumotórax, Queixo pontudo, Orelhas giradas posteriormente, Lóbulo da orelha grande, Apneia obstrutiva do sono, Cardiomiopatia hipertrófica, Hipoglicemia , Unhas dos pés hipoplásicas, Palato alto, Hidrocefalia, Voz rouca, Hiperextensibilidade das articulações dos dedos, Atraso de desenvolvimento global, Comprometimento cognitivo, Hipertelorismo, Hiperpigmentação da pele, Hiperqueratose, Hiperpigmentação generalizada, Ponte nasal deprimida, Bochechas cheias, Unhas frágeis, Acantose nigricante, Baixa estatura, narinas antevertidas, inserção baixa, orelhas giradas posteriormente, orelhas inseridas baixas, Macroglossia, face grande, hipermobilidade articular, falta de elasticidade da pele, movimento limitado do cotovelo, prolapso da válvula mitral, micrognatia, nevo, anormalidade do esmalte dentário, arritmia , Dermatoglifos anormais, Deficiência intelectual, Morfologia anormal do palato, Mo válvula pulmonar anormal rfologia, mitra anormal
Como alguém faz o teste de Costello síndromes?
O teste inicial para a
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 Costello síndromes
The clinical presentation of Costello syndrome is variable and may include coarse facial features (full lips, large mouth, full nasal tip); postnatal feeding difficulties accompanied by failure to thrive; short stature; developmental delay or intellectual disability; curly or sparse hair; skin papillomata; joint laxity; ulnar deviation of the wrist; and cardiac abnormalities, such as hypertrophic cardiomyopathy. The syndrome is caused by heterozygous mutations in the HRAS gene. A high birth weight, a vertical talus, dislocated hips, and acanthosis nigricans appear to be part of the condition. While the resemblance to Noonan syndrome still holds, the facial appearance does appear to become coarser with age, and significant intellectual disability can be a feature.
Joint laxity and abdominal hernias may also be features. Swallowing difficulties can be marked. There are many similarities to leprechaunism during this phase of the condition. Later on, the facial features become coarser, and there may be disproportionate weight gain relative to linear growth.
Features can be subtle, such as curly hair, mild facial features, and relative macrocephal. Even normal intelligence does not exclude the diagnosis.
Der Kaloustian et al. (1991) reported a further case with extensive perioral and perianal papillomata and hyperkeratosis of the palms and soles.
Zampino et al. (1993) reported two affected sibs and a further case. They provide an excellent review of the condition. They point out that in infancy there might be marked failure to thrive with reduced subcutaneous fatty tissue and muscle mass. The hair at this stage may be thin and sparse and the skin redundant with hyperpigmentation.
Hypertrophic cardiomyopathy has been reported (Philip and Mancini, 1993, and Lyn et al. 2002), as well as thickening of the mitral valves and arrhythmias (Izumikawa et al. 1993).
Siwik et al. (1998) review the cardiac abnormalities in this condition. Hypertrophic cardiomyopathy is reported in about 20-30% of cases. Other cases have VSD, PS, and ECG abnormalities.
Bird (David Smith meeting, 1999) reported a case with growth hormone deficiency.
Philip and Sigaudy (1998) and van Eeghen et al. (1999) provide good reviews. Hennekam (2003) provides a good total overview.
Kerr et al. (1998) reported two cases with an embryonal rhabdomyosarcoma, and a further case was reported by Feingold (1999). Sigaudy et al. (2000) reported six patients, including one with an embryonal rhabdomyosarcoma. Franceschini et al. (1999) reported a case who developed a bladder carcinoma. Other tumors may be present, including epithelioma (Martin and Jones, 1991) and ganglioneuroblastoma (Zampino et al. 1993; Moroni et al. 2000). The parents were first cousins once removed.
Van den Bosch et al. (2002) reported monozygotic twins with the condition diagnosed prenatally at 16 weeks of pregnancy because one had nuchal oedema, but no photographs were published.
Delrue et al. (2003) review brain-imaging findings in the condition. Ventricular dilatation is observed in more than 40% of cases. Other reported cerebral anomalies are brain atrophy, Chiari malformation and syringomyelia. Progressive cerebellar enlargement, with posterior fossa crowding, can result in cerebellar tonsillar herniation and was found in 96% of cases (Gripp et al., 2010).
Legault et al. (2001) reported a further case with growth hormone deficiency, as did Okamoto et al. (1994), Gregersen and Viljoen (2004), and Stein et al. (2004).
Gripp et al. (2002) reported five further cases with a rhabdomyosarcoma and recommended a screening protocol. This consisted of ultrasound examination of the abdomen and pelvis every three to six months until age 8 to 10 years for rhabdomyosarcoma and abdominal neuroblastoma. Also, urine catecholamine metabolite analysis every six to 12 months until the age of 5 for neuroblastoma and urinalysis for hematuria annually for bladder carcinoma after the age of 10 years.
See also the comments by DeBaun (2002) on screening for cancer in Costello syndrome.
Kaji et al., (2002) reported a case with glycogen storage disease type III who had features of Costello syndrome. Although several patients with Costello syndrome who also had hypoglycemia have been reported, the fundamental cause is not known, and no enzymatic defects have been found (reviewed by Kaji et al. 2002). Two children with hyperinsulinemic hypoglycemia were reported by Alexander et al. (2005).
Di Rocco et al. (1993) reported two cases with repeatedly raised sialic acid levels in the urine. Some cases have been reported to have an unusual ""mousy"" odor. Gripp et al. (2004) have provided evidence of an abnormal catecholamine metabolism (raised VMA and HVA).
Kerr et al. (2003) reported on children treated with growth hormone (GH). Progression of cardiomyopathy while on treatment occurred in one, and in the other, an embryonal rhabdomyosarcoma was diagnosed. The authors conclude that the use of GH requires further careful study and should only be undertaken with thorough explanation of the possible risks and close monitoring. Kerr et al. (2003) showed loss of heterozygosity (LOH) at 11p15.5 in embryonal rhabdomyosarcoma (E-RMS) tumor samples from five patients. They hypothesize that LOH at 11p15.5 is causally related to the genetic basis of the condition; however, a constitutional deletion at this locus was excluded in a series of patients.
Kamoda et al. (2003) reported a 5-year-old boy who developed osteofibrous dysplasia of the tibia while on growth hormone therapy. This disappeared upon cessation of the treatment.
White et al. (2005) described the adult phenotype in 17 adults and found two with a bladder carcinoma and two women with multiple ductal papillomata. The papillomata recurred after surgery. Three cases had a Chiari malformation, and several had osteoporosis. Excessive sweating of the palms of the hands was a major problem in a number of patients.
A moyamoya-like condition was described by Shiihara et al. (2005).
Lo et al. (2008) emphasize how difficult the diagnosis is when the neonatal phenotype is severe (hypoglycemia, cardiomyopathy, airway obstruction, pleural and pericardial effusions might predominate). The boundaries of this syndrome seem to be expanding and are becoming blurred. For example, the report by Kawame et al. (2003) includes seven out of 10 patients without skin papillomas.
A case reported by O'Shea et al. (2008) had persistent pulmonary hypertension.
Peculiar tongue movements during sleep occurred in four (9-31 months old) children (out of 10) reported by Della Marca et al. (2006).
Tartaglia et al., (2003) studied 27 cases with features of the condition but found no evidence for PTPN11 mutations.
Mutations in the HRAS proto-oncogene have been reported (Aoki et al., 2005). These authors hypothesized that genes mutated in Costello might be upstream or downstream of SHP-2 (involved in Noonan syndrome), so they sequenced the entire coding region of the four RAS genes. Mutations in HRAS were found in 12 of 13 patients.
Ioan and Fryns (2002) reported a pair of siblings whose mother had minor features of the condition. Note the patient reported by Gripp et al. (2006), also without a mutation, but who turned out to be mosaic for the HRAS mutation, picked up on buccal smear. The mother of the sibs reported by Gripp et al. (2011) was presumed to have germ cell mosaicism. Another case inherited from a father with somatic mosaicism was reported by Sol-Church et al., (2009).
Gripp et al. (2006) looked at 34 North American and four European patients and found mutations in 33. All mutations affected either codons 12 or 13.
Estep et al. (2006) found in a similar study that 91% had a 34G>A transition in codon 12. This latter group found no mutations in CFC syndrome.
Patients with CFC syndrome have been misdiagnosed as having Costello syndrome. Eighty-six percent of 43 patients studied by Kerr et al., (2006) were found to have HRAS mutations. Fifty-seven percent of those (seven cases) with the G12A mutation developed a malignancy.
Nava et al. (2007) suggest that the diagnosis of Costello syndrome should be limited to those with HRAS mutations.
In a series of patients with a KRAS mutation, the clinical phenotype ranged from Noonan to CFC and even Costello syndrome (Zenker et al., 2007).
van der Kaay et al. (2016) described four patients with RASopathy and precocious puberty. Two were diagnosed with Costello syndrome and had heterozygous missense mutations in the HRAS gene. Clinical characteristics included short stature, advanced bone age, and elevated basal LH and testosterone levels. No brain abnormalities were observed on MRI.
Pelc et al. (2016) described eight Polish patients with Costello syndrome and HRAS mutations. All patients shared the typical Costello features, including coarse facial appearance, failure to thrive, cardiac and skin anomalies, and intellectual disability. One male had a severe presentation of the syndrome, with congenital airway obstruction and cardiac hypertrophy, stenosis of the trachea (which required mechanical ventilation and tracheostomy), seizures, and early death at the age of 8 months due to cardiorespiratory failure.
Chiu et al. (2016) described a patient with Costello syndrome with severe malnutrition due to oromotor dysfunction. Additional features included hypotonia, transient hypoglycemia, gritty hair, frontal bossing, pointed chin, deep-set eyes, anteverted nostrils, and low-set ears. At 9 months, nutritional status was optimized, and typical dysmorphic features evolved, including thick lips, full cheeks, downslanting palpebral fissures, depressed nasal bridge and coarse facies.
Gripp et al. (2017) described an infant with severe feeding difficulties, failure to thrive, and hypertrophic cardiomyopathy carrying a novel de novo HRAS mutation (p.Gly60Val). The boy showed subtle dysmorphic features, including the wide mouth when smiling, prominent philtrum, and mildly deep palmar creases. He did not have ulnar deviation of his wrists. He died at age 8 months from a presumed cardiac cause.
Chiu et al. (2017) described a patient from a non-consanguineous family with a de novo missense mutation in codon 146 of the HRAS gene. He had failure to thrive and moderate global developmental delay. Brain MRI at 9 months showed an arachnoid cyst at the left posterior cranial fossa. Facial dysmorphism included frontal bossing with sparse and short hair, long eyelashes, deep-set eyes, low-set ears, short nasal tip, and a long philtrum. In addition, he had dry skin and inguinal hernia. Echocardiogram at the age of 3 years showed hypertrophic obstructive cardiomyopathy. The authors reviewed previously reported cases with the p.Ala146Pro mutation.
Pierpont et al. (2017) described two unrelated patients with Costello syndrome due to the HRAS p.Gly13Cys mutation and ophthalmologic findings. Both patients were born with weight above the 97th percentile and presented with hypoglycemia after birth, failure to thrive, and mild developmental delay. Nystagmus, photophobia, and vision abnormalities were noted. Ocular evaluation showed rod-cone retinal dystrophy, including attenuation of retinal vessels, atrophic retinal pigment epithelium, and hyperpigmented (Patient 1) or granular (Patient 2) retinal pigment epithelium. ERG changes were consistent with a progressive rod-cone retinal dystrophy.
Sánchez-Montenegro et al. (2017) reported two patients with Costello syndrome who developed umbilical ligament rhabdomyosarcoma. The authors reviewed 26 previously reported cases with Costello syndrome and rhabdomyosarcoma. The age at diagnosis of the tumor was between 6 months and 6 years. Initial symptoms included abdominal mass, abdominal pain, constipation, nausea, dysuria, or renal insufficiency. Location was mostly at the median umbilical ligament; histology type included embryonal (12), spindle cell (1), and alveolar (1) types.
* This information is courtesy of the L M D.
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