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At a glance

A syndrome characterized by postnatal growth deficiency, coarse facies, skin, cardiac and musculoskeletal anomalies, developmental delay, and papillomata.

Synonyms

Fasciocutaneoskeletal Syndrome; Mental Retardation Papillomata Syndrome; AMICABLE Syndrome (an acronym that stands for Amicable personality, Mental retardation, Impaired swallowing, Cardiomyopathy, Aortic defects, Bulk, Large lips and lobules, Ectodermal defects).

Incidence

The estimated birth prevalence is in the range of 1-3:1,000,000 in the general population. Approximately 300 cases have been described in the literature.

Genetic inheritance

Autosomal dominant, but most cases are sporadic. Penetrance is complete. The disorder is caused by mutations in the HRAS (V-HA-RAS Viral Homolog of Harvey Rat Sarcoma Oncogene; HRAS-proto-oncogene, GTPase) gene, which has been mapped to chromosome 11p15.5.

Pathophysiology

Costello Syndrome is considered a RASopathy, due to the mutations affecting the HRAS gene. RASopathies refer to a class of developmental disorders caused by activating germ-line mutations in genes that encode components or regulators of the RAS/mitogen-activated protein kinase pathway and are activated by extracellular input in the form of growth factors. These pathways are crucial in the regulation of cell cycles and cellular growth, differentiation, apoptosis, and senescence. The mutations leave HRAS activated for a prolonged time, which results in the abnormal development of multiple organ systems including the brain, heart, skin, and connective tissues. Fibroblasts show increased proliferation, normal elastin gene expression, produce normal amounts of tropoelastin, and properly deposit an extracellular microfibrillar scaffolding; however, the assembly of elastic fibers is defective secondary to rapid shedding of elastin binding proteins. This finding has been suggested to result from accumulation of chondroitin sulfate moieties, a phenomenon also found in ☞Mucopolysaccharidosis. Other RASopathies (among others) include ☞Noonan Syndrome, ☞Neurofibromatosis Type I, ☞LEOPARD Syndrome (Noonan Syndrome with Multiple Lentigines), and Cardio-Facio-Cutaneous Syndrome.

Diagnosis

Based on the clinical findings with typical facies, and ectodermal involvement (loose and hyperpigmented skin, papillomata). The diagnosis is confirmed by molecular genetic testing.

Clinical aspects

Pregnancy is frequently (in >90%) complicated by polyhydramnios and almost 60% of patients are born prematurely. Respiratory distress immediately after birth and in the neonatal period is frequent (in 63% of patients) with significant desaturations/cyanosis secondary to upper and/or lower airway obstruction (macroglossia, laryngo- and tracheomalacia, subglottic stenosis, poor control of oral secretions requiring frequent suctioning, or pleural effusions) and recurrent apneas requiring noninvasive positive pressure ventilation (eg, CPAP, BiPAP), prolonged endotracheal intubation or even tracheostomy. These symptoms persist beyond the neonatal period in some patients. In addition, a number of pulmonary malformations have been described, including lung hypoplasia, vascular dysplasia, bronchopulmonary dysplasia, congenital alveolar dysplasia, congenital pulmonary lymphangiectasia, and alveolar-capillary dysplasia have been described. Obstructive sleep apnea Syndrome is a common feature. Characteristically, these patients are born with increased ...

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