2024.04.29 | Questions 79-81
Cardiovascular genetics (2/3) - A girl with cardiomyopathy (& Aug 2024 ABGC Board Review Course!)
Hello,
This is the 2nd in a series of 3 posts related to cardiovascular genetics. I will discuss the case of a girl affected by a RASopathy, a class of disorders that are associated with cardiomyopathy and other structural heart differences. An audio version of this post is also available.
Also, we have 2 exciting announcements 📢:
Signups for the 30-hour ABGC Board Review Bootcamp in preparation for the August 2024 exam are now open! The course will take place June 13th - July 25th, 2024. Lynsey Rodriguez, MS, LCGC and I are excited to work with you. The signup page and the flyer below have more information about the course, and testimonials from our recent courses are available on our website. A discount is available for folks who sign up before June 1st. Please reach out with any questions (daniel@studyrare.com).
We are excited to announce the StudyRare ABGC board exam scholarship for GC students in need who are taking the August 2024 board exam. This scholarship covers the cost of the ABGC exam registration and the bootcamp this summer. Apply by May 24th. Please share this with anyone in your network who might be eligible.
I hope you have a great week!
-Daniel
Questions
Question 79
An 11-year-old girl with mild intellectual disability presents to the cardiology clinic for a follow-up visit. She was diagnosed with hypertrophic cardiomyopathy as an infant. Physical exam shows short stature and several scattered facial papillomas. Genetic testing is performed and shows a variant in HRAS, consistent with the diagnosis of Costello syndrome. Her parents should be advised about the risk of which of the following?
Question 80
Which of the following types of HRAS variants is most likely to be seen in a patient with Costello syndrome?
Question 81
The girl returns to the cardiology clinic 2 years later. The girl’s mother, Sally, is currently 10 weeks pregnant and has a new partner, Tim, who she has been with for the past year and who is not the girl’s biological father. Both Sally and Tim are healthy and have no known medical conditions. Neither parent has had genetic testing. Sally asks about the risk that her current pregnancy is affected with Costello syndrome. Which statement would be the MOST appropriate answer to share with the patient?
Explanations
Question 79: Bladder cancer
Question 80: p.G12S (missense)
Question 81: “The recurrence risk is 1-2%.”
Costello syndrome is a multi-systemic disorder that is associated with the “7 C’s”: Cardiac involvement🫀, ↑ Cancer risk🎗️, Craniofacial & skeletal differences💀🦴, Cerebrum (intellectual disability) & Cerebellum (Chiari I malformation) 🧠, Cutaneous manifestations (skin findings), and Cryptorchidism (in males). The most common cardiac findings in Costello syndrome include hypertrophic cardiomyopathy (HCM), which this patient has, and pulmonic stenosis. HCM can be progressive over time and requires routine follow up with cardiology. Cancer risks include neuroblastoma and rhabdomyosarcoma in young children, as well as bladder carcinoma (Question 79) in adolescents and young adults. Craniofacial and skeletal differences in patients with Costello include short stature, joint laxity, and scoliosis. Patients may have developmental delays and mild to moderate intellectual disability and are at risk for developing a Chiari I malformation. Skin findings may include hyperkeratosis and calluses, loose skin, and papillomas of the face or perianal region starting in childhood. Cryptorchidism, or undescended testes, are a common finding in males with Costello syndrome.
💡Note that many of these “7 C’s” are also common to other RASopathies, which are disorders due to variants in genes that encode proteins within the RAS/MAPK pathway (picture below). For example, the more common types of cardiac involvement seen in Costello syndrome (e.g., pulmonic stenosis, hypertrophic cardiomyopathy) are also highly prevalent in Noonan syndrome and cardio-facio-cutaneous syndrome.
Molecular genetics of Costello syndrome
Costello syndrome is most often caused by de novo missense variants in the gene HRAS, a GTPase protein that, when active, promotes cell growth. Most of these missense variants (~95%) affect amino acids 12 or 13 of the HRAS gene (Question 80) and are therefore examples of “hotspot” mutations, whereby a recurrent genetic change in the same position in the same gene results in the same disease. Variants like p.Gly12Ser disrupt GTPase function and impair the protein's ability to deactivate downstream protein signaling (kind of like a light switch💡 that is stuck in the “on” position). Consequently, there is continuous activation of the RAS/MAPK pathway, leading to uncontrolled cell proliferation. This persistent cell growth contributes to several characteristics seen in Costello syndrome, including an increased risk for certain cancers (e.g., rhabdomyosarcoma, neuroblastoma, and bladder), the development of benign papillomas on the face and perianal region, overgrowth of the cerebellum (resulting in Chiari I malformation), and overgrowth of heart muscle (leading to hypertrophic cardiomyopathy).
Inheritance of Costello syndrome
The vast majority of cases of Costello syndrome are due to de novo variants in HRAS. Therefore, the recurrence risk for siblings is low, but not zero. This is due to the risk of germline mosaicism, typically quoted at 1-2% (Question 81), which results in only the germ cells (egg or sperm) harboring the HRAS variant. While germline mosaicism cannot be directly tested for, it is presumed to be present if there are multiple siblings with the same genetic condition in a family where both parents have tested negative for the variant in blood or saliva. There is increasing evidence that most de novo variants resulting in Costello and other RASopathies are due to variants in sperm and therefore arise from the paternal lineage. Some cases of Costello also may arise from somatic mosaicism, where a genetic mutation in HRAS arises post-zygotically.
Screening and management recommendations for Costello syndrome
Due to the increased risk of benign and malignant tumors, including rhabdomyosarcoma and bladder cancer (Question 79), individuals with Costello syndrome require regular screening and monitoring for cancer and heart disease. Cancer screening may include periodic abdominal and pelvic ultrasound to screen for rhabdomyosarcoma and neuroblastoma until the age of 10 years (after which the risk for these cancers decreases). In addition, an annual urinalysis to check for hematuria, a sign of bladder cancer, can be performed starting at age ten years. Routine cardiac follow up even in patients without known cardiac disease is also important due to the risk of hypertrophic cardiomyopathy, which can be progressive and life-threatening. For patients with severe cardiomyopathy, treatment with trametinib, an inhibitor of the RAS/MAPK pathway, may reduce the degree of cardiomyopathy. More broadly, there are efforts to repurpose approved anti-cancer therapeutics that inhibit RAS/MAPK signaling to help treat some of the complications of the RASopathies.
Incorrect answers
Question 79
Spontaneous pneumothorax (Choice A) can be seen in Marfan syndrome, a connective tissue disorder affecting the skeleton, eye, and aorta. The risk for pneumothorax is not increased in Costello syndrome. Progressive neurological decline (Choice C) is not typically associated with Costello syndrome, which is instead characterized by developmental delays and non-progressive intellectual disability. Progressive neurological decline can be observed in lysosomal storage disorders such as Tay-Sachs disease, which is characterized by the progressive buildup of toxic metabolites within neurons. Early menopause (choice D) can be seen in Turner syndrome, a condition affecting females that is also associated with short stature and cardiac anomalies, and is not a feature of Costello syndrome.
Question 80
Frameshift variants (p.Leu69HisfsTer10, Choice A) often result in stop-gain variants that truncate the protein prematurely and result in haploinsufficiency. While many genetic disorders can be due to haploinsufficiency (loss of 50% of the normal amount of protein expressed; think “half”-loinsufficiency), Costello syndrome is due to gain-of-function rather than haploinsufficiency. In-frame deletions, which result in the loss of 1 or more amino acids, are not well-established causes of Costello syndrome. The in-frame deletion (p.Tyr157del) in Choice B results in the loss of 1 amino acid and is seen in the general population. Splice site variants that do not occur at canonical splice donor or acceptor site (e.g., c.451-9C>T, Choice D) are more difficult to interpret in terms of their clinical significance and are often not clearly pathogenic. Splice site variants are not well-established causes of Costello syndrome.
Question 81
A recurrence risk of 50% (Choice A) is seen with disorders inherited in an autosomal dominant manner. Costello syndrome is usually not inherited and typically occurs de novo in a child. While transmission of Costello from an affected parent to child is technically possible, the likelihood that either parent carries the HRAS variant is quite low in this case given their lack of symptoms and the fact that Costello syndrome has near-complete penetrance (~100%). If germline mosaicism for an HRAS variant were present (~1-2% of cases), then the recurrence risk for each pregnancy would be 50%. Testing Tim (Choice B), the new partner of the mother, would be needed to assess risk if the disorder in question were inherited in an autosomal recessive manner. Costello syndrome is not sex-linked and affects males and females equally (Choice D).
Learning objective
Costello syndrome, characterized by the "7 C’s," is a multi-systemic disorder caused by de novo, gain-of-function variants in the HRAS gene. These variants activate the RAS/MAPK signaling pathway and promote uncontrolled cell growth. This excessive cell growth underlies several clinically-important features seen in Costello syndrome, including a predisposition to cancer, skin papillomas, hypertrophic cardiomyopathy, and Chiari I malformation. Routine surveillance for certain cancers and cardiac complications such as hypertrophic cardiomyopathy is recommended. Costello syndrome shares clinical overlap with other RASopathies (e.g. Noonan, cardio-facio-cutaneous syndrome), which are disorders characterized by constitutional variants that activate the RAS/MAPK signaling pathway.
2023 ABMGG General Exam Blueprint | V. Single gene inheritance → d. Single gene disorders → iii) Cardiac disorders
2023 ABGC Exam Content Outline | Domain 1C. Genetic Conditions → 1. Clinical features, 5. Management options, and 8. Etiology
References
Costello syndrome (GeneReviews)
RASopathies and cardiac manifestations (2023 review article)
RASopathies network (patient advocacy group)