MedGen

While the majority of individuals with Costello syndrome share characteristic findings affecting multiple organ systems, the phenotypic spectrum is wide, ranging from a milder or attenuated phenotype to a severe phenotype with early lethal complications. Costello syndrome is typically characterized by failure to thrive in infancy as a result of severe postnatal feeding difficulties; short stature; developmental delay or intellectual disability; coarse facial features (full lips, large mouth, full nasal tip); curly or sparse, fine hair; loose, soft skin with deep palmar and plantar creases; papillomata of the face and perianal region; diffuse hypotonia and joint laxity with ulnar deviation of the wrists and fingers; tight Achilles tendons; and cardiac involvement including: cardiac hypertrophy (usually typical hypertrophic cardiomyopathy), congenital heart defect (usually valvar pulmonic stenosis), and arrhythmia (usually supraventricular tachycardia, especially chaotic atrial rhythm/multifocal atrial tachycardia or ectopic atrial tachycardia). Relative or absolute macrocephaly is typical, and postnatal cerebellar overgrowth can result in the development of a Chiari I malformation with associated anomalies including hydrocephalus or syringomyelia. Individuals with Costello syndrome have an approximately 15% lifetime risk for malignant tumors including rhabdomyosarcoma and neuroblastoma in young children and transitional cell carcinoma of the bladder in adolescents and young adults. [from GeneReviews]

Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins. Type I CDGs comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein. These disorders can be identified by a characteristic abnormal isoelectric focusing profile of plasma transferrin (Leroy, 2006). For a discussion of the classification of CDGs, see CDG1A (212065). CDG Ib is clinically distinct from most other CDGs by the lack of significant central nervous system involvement. The predominant symptoms are chronic diarrhea with failure to thrive and protein-losing enteropathy with coagulopathy. Some patients develop hepatic fibrosis. CDG Ib is also different from other CDGs in that it can be treated effectively with oral mannose supplementation, but can be fatal if untreated (Marquardt and Denecke, 2003). Thus, CDG Ib should be considered in the differential diagnosis of patients with unexplained hypoglycemia, chronic diarrhea, liver disease, or coagulopathy in order to allow early diagnosis and effective therapy (Vuillaumier-Barrot et al., 2002) Freeze and Aebi (1999) reviewed CDG Ib and CDG Ic (603147). Marques-da-Silva et al. (2017) systematically reviewed the literature concerning liver involvement in CDG. [from OMIM]