RASopathies: Dermatologists’ viewpoints

Ras/mitogen-activated protein kinase pathway dysregulation results in a group of disorders, collectively termed as RASopathies. Neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentigines, Noonan syndrome/loose anagen hair, Legius syndrome, Costello syndrome, cardio-facio-cutaneous syndrome and capillary malformation-arteriovenous malformation are the well- recognized RASopathies. These are characterized by multi-organ tumours and hamartomas. Some other features in common are facial dysmorphism, skeletal abnormalities, congenital heart disease, neurocognitive abnormalities and risk of various solid-organ and haematological malignancies. Some of the RASopathies are heterogeneous, caused by several gene mutations resulting in variations in phenotypes and severity ranging from mild to fatal. Significant phenotypic overlaps among different disorders, often makes it difficult to pinpoint a clinical diagnosis. Specific cutaneous manifestations are present in some of the RASopathies and are often the earliest clinical signs/symptoms. Hence, dermatologists contribute significantly as primary care physicians by identifying disorder-specific cutaneous lesions. However, diagnostic work-up and management of these disorders are often multidisciplinary. Confirmation of diagnosis is possible only by genetic mapping in each case. Genetic counseling of the patients and the affected families is an important component of the management. The aim of this review is description of cutaneous manifestations of RASopathies in the background of multi-system involvement to enable dermatologists a comprehensive and logical approach to work up and diagnose such patients in the absence of facility for specific molecular testing.

A Case of Costello Syndrome with Severe Palmoplantar Keratoderma / 대한피부과학회지

No abstract available.

Mutation detection in a case of Costello syndrome complicated by cutis laxa / 中华皮肤科杂志

Objective To report a case of Costello syndrome complicated by curis laxa,and to make a molecular genetic diagnosis.Methods Clinical data were collected from a case of Costello syndrome complicated by cutis laxa.Skin tissues were resected from the patient,and peripheral blood samples were obtained from the patient's parents and 150 unrelated healthy controls.Genomic DNA was extracted from these samples,and all the exons and their flanking sequences of the HRAS gene were analyzed by DNA sequencing.Results The 13-month-old female patient presented with growth retardation,severe malnutrition,coarse facial appearance,severely loose skin over the limbs,and decrease or disappearance of subcutaneous fat.A heterozygous mutation c.34G ＞ T (p.Gly12Cys) was detected in exon 2 of the HRAS gene in the patient,but not in her parents or 150 unrelated healthy controls.Conclusion The c.34G ＞ T (p.Gly12Cys) mutation in exon 2 of the HRAS gene may be responsible for Costello syndrome in the patient.

Syndrome in question

Costello syndrome (CS) is a rare genetic disorder, first described by Costello in 1971, caused by mutations in the HRAS proto-oncogene. Clinical findings include facial dysmorphism, skin disorders, cognitive impairment, cardiac and musculoskeletal defects. There is an increased risk of malignancies in these patients, due to the proto-oncogene mutation, and also sudden death secondary to heart disease. We report a case with characteristic phenotype, highlighting the peculiar skin changes.

Síndrome de Costello. Presentación de un caso / Costello Syndrome. A case report

El síndrome de Costello es una enfermedad congénita y multisistémica, extremadamente rara; se describen en la literatura alrededor de 250 casos. Se plantea que el patrón de herencia es autosómico dominante, aunque muchos de los casos son esporádicos, sugiriendo una mutación dominante de novo. Se presenta el caso de un paciente masculino de siete años de edad, natural del municipio Frank País, Holguín, con manifestaciones clínicas compatibles con el diagnóstico de síndrome de Costello. Se realizó estudio y descripción clínica del hábito externo, detectándose como principales rasgos distintivos: fenotipo pseudotesaurismótico, déficit del crecimiento, cardiopatía congénita, facies grotesca, retardo mental y personalidad humorística. El diagnóstico precoz de este síndrome, hace posible la estimulación e intervención temprana, la búsqueda activa de lesiones tumorales, así como ofrecer asesoramiento genético a los padres.

Costello syndrome is an extremely rare multisystem congenital disorder; only about 250 cases have been described in the literature. Its inheritance pattern is considered to be autosomal dominant, although most cases are sporadic, suggesting de novo dominant mutations. The case of a 7-year-old patient from the Frank País municipality in Holguín with clinical manifestations consistent with Costello syndrome is presented. The clinical study and description of his physical characteristics were performed, detecting as main distinctive features: storage disease-like phenotype, failure to thrive, congenital heart disease, coarse facies, mental retardation and humorous personality. Early diagnosis allows early stimulation and intervention, active screening for tumor lesions, as well as provision of genetic counselling to patients.

Ross operation in a neuro-cardio-facial-cutaneous syndrome patient.

Congenital heart diseases are a major part of Costello and cardio-facio-cutaneous syndromes. Subaortic stenosis was reported rarely and Ross operation never in these syndromes. We reported a girl patient whose manifestations were consistent with these syndromes. Distinction between these syndromes was not possible as genetic testing was not carried out. She developed severe neoaortic regurgitation 2.5 years after the Ross operation and died due to the complications of aortic valve replacement. Ross operation may be an unsuitable option in these syndromes due to the possibility of subtle pulmonic valve pathology.

Habilidades funcionais e desempenho motor em uma criança com síndrome de costello: relato de caso / Functional abilities and motor performance in a child with Costello syndrome: case report

Este estudo objetivou caracterizar as habilidades funcionais e o desempenho motor de uma criança de cinco anos de idade com Síndrome de Costello (SC), classificada no nível III quanto ao Gross Motor Function Classification System (GMFCS). As avaliações foram realizadas no Núcleo Educacional e Terapêutico Vida em Movimento, Paulinia, SP. Para avaliar as habilidades funcionais da criança empregou-se o Pediatric Evaluation Disability Inventory (PEDI,) e para avaliar o desempenho motor aplicou-se o Gross Motor Function Measure (GMFM). Quanto as habilidades funcionais avaliadas, a criança apresentou melhor desempenho na área de função social: 24 (36,9%); quanto ao desempenho motor, obteve melhor desempenho nas dimensões A (deitar e rolar): 42 (82,3%) e B (sentar): 40 (66,6%). Tais avaliações são confirmadas por sua classificação no nível III do GMFCS, caracterizada pelo controle nas posturas sentada e de pé e pela deambulação com auxilio de suporte.

This study aimed at characterizing functional abilities and motor performance of a five-year-old child with Costello Syndrome (CS), classified as level III in Gross Motor Function Classification System (GMFCS). Evaluations were performed at the Núcleo Educacional e Terapêutico Vida em Movimento, Paulínia, SP. The Pediatric Evaluation Disability Inventory (PEDI) was used to evaluate child's functional abilities and the Gross Motor Function Measure (GMFM) was applied to evaluate the motor performance. According to the functional abilities, the child performed better in social function area: 24 (36.9%); according to the motor performance, she performed better in dimensions A (lie down and roll): 42 (82.3%) and B (sit down): 40 (66.6%). These evaluations are confirmed by the child's classification at level III in GMFCS, characterized by the seated and standing postures control and by walking with some aiding support.

Costello syndrome: three sporadic cases / 소아과

Costello syndrome (CS) is a rare multiple congenital abnormality syndrome characterized by a typical coarse face, developmental delay, psychomotor and growth retardation, neurologic abnormalities, cardiac and cutaneous anomalies, severe feeding difficulties with postnatal growth failure, and increased risk of tumors. Since Costello first described it in 1971 and again in 1977, over 100 cases have been reported worldwide. It was recently shown that CS is a congenital condition caused by heterozygous de novo missense mutations affecting the codon for glycine 12 or 13 of the HRAS gene. We experienced three unrelated cases with coarse faces, developmental delays, short statures, macrocephaly, and redundant skin with deep palmar and plantar creases, hypertrophic cardiomyopathy and atrial tachycardia, which are characteristic of CS.