ID #1003

What is the history of its description over the years?

First description: In 1975 and1977, Dr. Jack Costello, a New Zealand pediatrician, published the descriptionof two children with similar physical characteristics and mild intellectualhandicap. 

Early Reports: In 1991, Dr. Vazken Der Kaloustian from Montreal reported a similar child and suggested that this particular pattern of physical and developmental characteristics be called Costello syndrome. Additional articles followed, and by 1996, when Dr. Costello published an update on his original cases, he included a review of 16 literature cases

Geneticists and other clinicians around the world continued to describe Costello syndrome in single patient reports, case series, and a few large reviews.  In addition to general descriptions, specialists focused on specific organs or issues.  A search of the genetic cause was always at the top of the research list of priorities. Also important was establishing diagnostic criteria (how to identify a child with the syndrome), because, as the cause was unknown, the diagnosis was based on presence or absence of certain clinical features.

The large number of publications over the last decade demonstrates the power of combined family and professional networking. These publications increased knowledge of the impact of Costello syndrome on the health and lives of children, adults, and their families.

Clinical genetic research: Until 2005, the cause of Costello syndrome remained unknown. Family studies had demonstrated that a new genetic change in the affected person was the likely cause (a ?spontaneous? or ?de novo? mutation). Since the cause was unknown, the diagnosis was based on the presence or absence of clinical features linked to Costello syndrome.

Molecular genetic research: In 2005, a group of Japanese researchers led by Drs. Aoki and Matsubara discovered that mutations (a gene change affecting a gene's  function) in a gene called HRAS causes Costello syndrome. It had been known for many years that Costello syndrome was similar to two other conditions, Noonan syndrome (NS) and Cardio-facio-cutaneous syndrome (CFC).  All three syndromes are now known to be part of the Ras/MAPK pathway.

Since that first publication, other genes in the pathway have been found to be important causes of both Noonan syndrome (NS) and Cardio=facio-cutaneous syndrome (CFC), two disorders that may resemble CS.  Many researchers have now molecularly tested groups of patients with a possible clinical diagnosis of CS, NS, or CFC.

HRAS is a gene that had been known about for a long time, because mutations in it are common in cancers seen in the general population. These mutations are said to arise somatically, this means they arose in a tissue in a person, ( eg bowel or lung) as an error in normal cell division. This is different to a gene mistake being present in an egg or sperm, and therefore in all cells in the body. These types of mistakes, in egg or sperm, are called germ-line, and this is the type of HRAS mutation seen in CS. It was a surprise that a cancer associated gene like HRAS could cause a developmental syndrome.

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