The Origins of CFC

Alexis Poss, MS, CGC
Duke University Medical Center

Unlike syndromes named for a particular doctor or even for a particular patient Cardiofaciocutaneous syndrome (CFC) gets its name from the parts of the body that were described as having differences: the heart, the face, and the skin. Why does it have this name? Who named it?

CFC has deep roots in the medical specialty of clinical genetics, and so we begin the story with the end of polio. In 1955 a vaccine against poliomyelitis was introduced, with 450 million doses administered in the United States over the next 4 years. A polio vaccine became standard among childhood immunizations, with its total eradication in the Americas in 1994.1 This work was funded in a remarkable way. President Franklin D. Roosevelt, himself a victim of polio, established the National Foundation for Infantile Paralysis in 1938. A celebrity of the day, Eddie Cantor, coined the phrase “March of Dimes” appealing to Americans to send dimes directly to the White House. This campaign was the birth of the organization we call the March of Dimes Foundation today.2

In 1958 the “expanded program” of the March of Dimes was announced. This would re-focus the foundation on birth defects prevention.3 It was an exciting time when (in 1951) it was shown that altering the diet of a child with phenylketonuria (PKU) could prevent mental retardation. Newborn screening for PKU became possible on a national scale in 1966.4 There was hope that birth defects might be eradicated too.

In 1968 the first Clinical Delineation of Birth Defects meeting was hosted by the March of Dimes and The Johns Hopkins Hospital.3 This important meeting brought together doctors interested in preventing birth defects and mental retardation. The first step was to systematically catalogue what they saw in Institutions and in their clinics. Begun in 1966, Dr. Victor McKusick from The Johns Hopkins Hospital published this catalogue, which is now continually updated and publicly available as the Online Mendelian Inheritance in Man.5 Today we recognize this as one of the most important foundations upon which the field of clinical genetics would be built.

The doctors who attended the March of Dimes Birth Defects Conferences in the late 1960s – early 1970s became the first generation of clinical geneticists (recognized as a specialty by the American Medical Association in 19916). They spoke frequently with one another, visited each other’s practices, and learned much from their collaborative efforts. From this group, or their disciples, seven doctors would write the first paper coining the term Cardio-Facio-Cutaneous (CFC) syndrome. They were Jim Reynolds (in Helena, Montana), Giovanni Neri (in Rome, Italy), Jürgen Herrmann (German-born, working in Wauwatosa,Wisconsin), Bruce Blumberg (in San Francisco, California), James Coldwell (in Tulsa, Oklahoma), Paul Miles (in Twin Falls, Idaho), and John M. Opitz (German-born, working in Helena, Montana).7   To be fair, we note that case reports of children with what would be called CFC today were previously published.8,9

The CFC story itself begins in the same year as the first gathering of doctors to discuss birth defects. In 1968 an 11-week old boy at the Wisconsin Orthopedic Hospital for Children, part of the University of Wisconsin, was sent to Dr. Opitz referred from the cardiology service. This baby was large, severely hypotonic, developmentally delayed, with sparse curly hair, ptosis, an abnormal EEG, possible heart defect, and hyperkeratosis of the skin which became worse with age. Then, in 1969 Dr. Opitz saw a 4½-month-old girl referred for a large cavernous hemangioma. She was thought to represent a variant of Noonan syndrome, although her appearance and constellation of congenital anomalies reminded Dr. Opitz of the boy he had seen the year before.   In 1971 a third child came to the Wisconsin clinic; this was a 3¾-year-old girl referred for developmental delays, heart defects, cavernous hemangioma, cleft palate, eye abnormalities, skin abnormalities, and spasticity.7 At this point Dr. Opitz suggested putting together a paper to share the similarities of these children with other doctors interested in clinical genetics, however this was not accomplished.10

In 1976 Dr. Phil Pallister saw a 2-year-old girl with the same condition7 in Montana (where Dr. Opitz would soon move his practice). This girl was more significantly delayed initially, although it is heartening to know that as an adult today she is living self-sufficiently and considers herself “perfectly normal.”10 In 1979, a separate group of geneticists led by Dr. Bruce Blumberg made a presentation at the March of Dimes Birth Defects Conference describing two children with “a new mental retardation syndrome with characteristic facies, ichthyosis, and abnormal hair.”11 Dr. Jim Reynolds, working with Dr. Opitz in Montana, started to put this together into a publication. This paper was submitted to a medical journal in 1985, was presented at an invitation-only meeting for leading clinical geneticists called the David W. Smith Workshop on Morphogenesis and Malformations in 198612, and then published in the same year. At the David Smith meeting 6 cases were presented; the publication contained 8 cases because cases were added following the presentation, including a 7-year old boy with this condition seen by Dr. James Coldwell of Oklahoma in 1983.

Following this publication Dr. Giovani Neri and his Italian colleagues published a report with the first two cases outside the United States, an 18-month old boy seen in 1985 and a 22-month old boy seen 1986.13 This was followed by a 1988 publication by Dr. Verloes and his Belgian and French colleagues on a girl of Greek descent ascertained at 8½-years and a girl seen at 3-years of age.14 These authors also pointed out that another 1986 publication by Drs. Baraitser and Patton in England called “A Noonan-like short stature syndrome with sparse hair” ought to be taken together with the Reynolds paper as further description of CFC syndrome.15 Five more cases were published in 198916,17,18, another two in 199019,20, and by 1991 debate was breaking out asking whether CFC should be considered a distinct syndrome. 21, 22, 23 Some doctors advocated that it was the same as Noonan syndrome, others that it was a separate syndrome.

Once the CFC syndrome was published in the late 1980s doctors around the world were able to start diagnosing children with the condition. Unfortunately, when parents would ask their geneticist for another family to talk to, there was no network available among the parents to offer support and hope. Around 1990 Mrs. Nancy Carlson wrote a letter to “Exceptional Parent” magazine, searching for another parent. Nancy’s daughter, Kristen, was born in 1987, diagnosed with Noonan when she was 2 years old, but then Nancy did her own research at the college library and saw that Noonan was not a perfect fit. Kristen’s cardiologist went to a medical conference where he learned of CFC syndrome and subsequently changed her diagnosis. Kristen’s geneticist apparently agreed that the diagnosis fit. Nancy started a correspondence with the families who responded to her letter in “Exceptional Parent.” Nancy describes some of those early telephone calls in which they joked that CFC might stand for “constantly facing challenges” or perhaps “children, funny children.” With this birth of a CFC syndrome family network Nancy began to regularly answer calls from newly diagnosed families and send out newsletters starting around October 1991. The cost of postage was getting expensive for this kitchen table non-profit, and so a listserv on YahooGroups was a welcome development. This made sharing information and support fast, easy, and free.

While this was going on from Nancy’s home in New Jersey, in New York Brenda and Cliff Conger were searching for a diagnosis for their son, born in 1993. Three years of investigation finally brought them to the diagnosis of CFC. Brenda then contacted Nancy through an ad in “Exceptional Parent” magazine, going on to take over the CFC support group from Nancy in 1997; at that time the family list included 21 names and addresses. Brenda attended advocacy training both hosted by the National Organization for Rare Diseases and by the Genetic Alliance to learn how to obtain more awareness for CFC syndrome. She incorporated the CFC Family Network in 1999 and created a vision for the organization. The vision included: a syndrome brochure, website, newsletters, Parent’s Guide, medical advisors, and eventually a conference.

The first CFC conference took place in July 2000 in Salt Lake City, Utah with 37 families attending, nearly the entire medical advisory board (Drs. Allanson, Carey, Kavamura, Neri, Noonan, and Opitz), rehabilitative medicine staff, local geneticists, and the leaders of the Noonan and Costello support organizations (Wanda Robinson and Colin Stone, respectively).   While discovering the genetic cause of CFC seemed a long way off at the time, the medical advisors were quite excited by this unique opportunity to hone their abilities to make a clinical diagnosis of CFC syndrome. Thus among all the discussions, lectures, examinations, blood draws, and other (fun) activities perhaps the most exciting was the opportunity to take photos of the children and then study them side by side. This parsing of CFC vs. Noonan vs. Costello vs. “other” was a key step forward for physicians making a clinical diagnosis of the condition.

By 2004 the support organization grew to close to 100 families representing nine different countries. Leadership by then encompassed an active Board of Directors. The Board changed the name from CFC Family Network to CFC International and introduced their new logo. After attending a training program in Washington, DC on advocacy organization biobanking, CFC International boldly moved forward to bank their own DNA through the jointly owned Genetic Alliance BioBank Program. This venture captured the attention of researchers from around the globe. By the fall of 2005, CFC International partnered with a team of researchers led by Dr. Katherine Rauen at the UCSF Comprehensive Cancer Center. Two years worth of clinical data and DNA storage paid off as the collaborative team efforts quickly located three of the genes responsible for CFC syndrome. Publication of the gene discovery occurred in one of the most highly visible formats in all of science and medicine in March 200624. Additional publications followed quickly, along with an NIH grant to host the first International Symposium on CFC and Noonan syndromes in November 2006. CFC International continues to collect clinical data and DNA with the hope to move research forward into treatment programs to help the next generation of affected children


  1. Department of Health and Human Services, Centers for Disease Control, National Immunization Program, April 13, 2005 “Background on polio vaccine.”

  2. March of Dimes, 2006 “The March of Dimes Story”

  3. March of Dimes Archives, Conferences and Meetings Records, 1938-2002;
    Series 7: Birth Defects/Clinical Genetics.

  4. BioMarin Pharmaceutical, Inc., 2006, “PKUnparalleled Progress”

  5. Online Mendelian Inheritance in Man

  6. American College of Medical Genetics, 2006 “History”

  7. Reynolds JF, Neri G, Herrmann JP, Blumberg B, Coldwell JG, Miles PV, and Opitz JM. New multiple congenital anomalies/mental retardation syndrome with cardio-facio-cutaneous involvement – the CFC syndrome. Am J Med Genet 1986; 28:413-427.

  8. Navarantnam AE. Ulerythema ophryogenes with mental retardation. Proc R Soc Med 1973; 66:233-234.

  9. Pierini DO & Pierini AM. Keratosis pilaris atrophicans faciei (ulerythema ophrogenes): a cutaneous marker in the Noonan syndrome. Br J Dermatol 1979; 100:409-416.

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  11. Blumberg B, Shapiro L, Punnett H, Rimoin D, and Kistenmacher M. A new mental retardation syndrome with characteristic facies, ichthyosis and abnormal hair. March of Dimes, Birth Defects Conference (Chicago, IL 1979); Abstract 105.

  12. Reynolds JF, Lewin SO, Herrmann J, Blumberg BD, and Opitz JM. Cutaneous manifestations of the Cardio-Facio-Cutaneous (CFC) syndrome: Differentiation from the Noonan syndrome. David W. Smith Workshop on Morphogenesis and Malformations (Burlington, VT 1986); p. 171.

  13. Neri G, Sabatino G, Bertini E, and Genuardi M. Brief Clinical Report: The CFC Syndrome – Report of the first two cases outside the United States. Am J Med Genet 1987; 27:767-771.

  14. Verloes A, LeMerrer M, Soyeur D, Kaplan J, Pangalos C, Rigo J, and Briard M-L. CFC Syndrome: A syndrome distinct from Noonan syndrome. Ann Génét 1988; 31:230-234.

  15. Baraitser M & Patton MA. A Noonan-like short stature syndrome with sparse hair. J Med Genet 1986; 23:161-164.

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  18. Sorge G, DiForti F, Scarano G, Ventruto V, Zelante L, and Dallapiccola B. CFC syndrome: Report on three additional cases. Am J Med Genet 1989; 33:476-478.

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  22. Neri G, Zollino M, and Reynolds JF. The Noonan-CFC controversy. Am J Med Genet 1991; 39:367-370.

  23. Verloes A and Le Merrer M. Lumping of CFC and Baraitser-Patton Noonan-like syndromes. Am J Med Genet 1992; 42:756.

  24. Rodriguez-Viciana P, Tetsu O, Tidyman WE, Estep AL, Conger BA, Santa Cruz M, McCormick F, and Rauen KA. Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science 2006; 311:1287-1290.