What are the clinical implications of a pathogenic RTEL1 (Regulator of Telomere Elongation Helicase 1) mutation and what evaluations and monitoring should be performed for affected individuals?

Clinical Implications of Pathogenic RTEL1 Mutations

Individuals with pathogenic RTEL1 mutations require immediate multidisciplinary evaluation and lifelong surveillance for telomere biology disorders, including pulmonary fibrosis, bone marrow failure, liver disease, and cancer predisposition. 1

Understanding RTEL1-Related Disease

RTEL1 (Regulator of Telomere Elongation Helicase 1) is a DNA helicase essential for telomere maintenance and genome stability. 2, 3 The clinical presentation depends critically on inheritance pattern:

• Heterozygous (autosomal dominant) mutations cause adult-onset telomeropathy with variable penetrance, primarily manifesting as pulmonary fibrosis, premature graying, and increased cancer risk 1
• Biallelic (autosomal recessive) mutations cause severe childhood-onset Hoyeraal-Hreidarsson syndrome with intrauterine growth retardation, bone marrow failure, microcephaly, cerebellar hypoplasia, and immunodeficiency 4, 5

RTEL1 accounts for 2-5% of familial pulmonary fibrosis cases. 1

Initial Diagnostic Evaluation

Genetic Testing Strategy

Order both comprehensive telomere-gene sequencing and leukocyte telomere-length measurement by flow-FISH simultaneously. 1

The sequencing panel must include RTEL1 plus TERT, TERC, PARN, DKC1, NAF1, ZCCHC8, NOP10, and TINF2. 1

Telomere Length Interpretation

• Below 1st percentile for age: Confirms dyskeratosis congenita and strongly supports telomeropathy diagnosis 1
• At or above 50th percentile: High negative predictive value; telomere disorder unlikely 6, 1
• Between 1st-50th percentile: Indeterminate; requires clinical correlation 1

Critical caveat: Normal telomere length does not exclude a pathogenic RTEL1 variant, especially in patients over 40 years, because shortening magnitude varies by specific gene and age at presentation. 1

Three-Generation Pedigree Assessment

Document the following in all first-, second-, and third-degree relatives: 1

• Pulmonary fibrosis (any age, but especially <50 years)
• Bone marrow failure, myelodysplastic syndrome, or acute myeloid leukemia
• Liver cirrhosis or unexplained hepatic dysfunction
• Head and neck cancers before age 50
• Premature hair graying (onset in teens or twenties)
• Nail dystrophy or oral leukoplakia

Look specifically for genetic anticipation: successive generations developing disease earlier and more severely. 6, 1, 7

Baseline Phenotypic Screening

Pulmonary Assessment

• High-resolution chest CT to establish baseline fibrosis pattern 1
• Pulmonary function tests (FVC, DLCO) 1
• Key point: Patients with telomere-gene variants experience rapid fibrosis progression and poorer survival compared to sporadic idiopathic pulmonary fibrosis 6, 1

Hematologic Evaluation

• Complete blood count with differential looking for macrocytosis, anemia, thrombocytopenia, or neutropenia 1
• Baseline bone marrow aspirate and biopsy to establish pre-disease state 6, 1
• Approximately 50% of dyskeratosis congenita patients develop bone marrow failure by age 40, which is the leading cause of mortality 6, 4

Hepatic Screening

• Comprehensive liver function tests (AST, ALT, alkaline phosphatase, bilirubin, albumin, INR) 1
• Consider abdominal ultrasound or elastography to assess for occult cirrhosis 1

Dermatologic Examination

• Inspect for lacy reticular pigmentation on upper chest or neck 6, 1
• Assess for nail dystrophy (part of classic dyskeratosis congenita triad) 6, 4
• Document premature alopecia or oral leukoplakia 1, 4

Skeletal Assessment

• Inquire about premature osteoporosis or avascular necrosis of hips/shoulders 1

Oncologic Baseline

• Establish heightened surveillance plan for head and neck squamous cell carcinoma (median onset 20-30 years in telomeropathies) 6, 4
• MDS/AML risk begins in late teens with median onset in 40s 6

Ongoing Surveillance Protocol

Annual Monitoring Requirements

Pulmonary (every 6-12 months): 1

• Pulmonary function tests
• Consider interval chest CT if symptoms progress

Hematologic (annually or more frequently if abnormal): 6, 1

• Complete blood count
• Annual bone marrow aspirate and biopsy for aplastic anemia or myelodysplastic syndrome surveillance

Hepatic (annually): 1

• Liver function tests
• Imaging if transaminases elevated

Oncologic (annually): 6, 1, 4

• Head and neck examination for squamous cell carcinoma
• Maintain high index of suspicion for solid tumors (cumulative incidence 20-30% by age 50)

Management Considerations

Pulmonary Fibrosis Treatment

• Standard antifibrotic agents (pirfenidone or nintedanib) may be used, though disease-specific outcome data in RTEL1 carriers are limited 1
• Consider early lung transplant evaluation due to propensity for rapid progression 1
• Avoid invasive surgical lung biopsy when genetic diagnosis is established, as histopathology is less prognostically informative and the variant itself predicts poor survival 6

Critical transplant caveat: Post-transplant complications including bone marrow failure and hepatic dysfunction are increased in telomeropathy carriers. 1

Medication Precautions

Avoid all myelosuppressive drugs due to underlying bone marrow vulnerability. 1

Family Counseling and Cascade Testing

Offer genetic counseling to all first-degree relatives immediately. 1, 7

Explain: 6, 1, 7

• Autosomal dominant inheritance with 50% transmission risk to children
• Variable penetrance (not all carriers develop disease)
• Genetic anticipation with progressive telomere shortening across generations
• Earlier onset and more severe manifestations in subsequent generations possible

Cascade testing of at-risk family members should be performed once the pathogenic variant is confirmed. 1

Multidisciplinary Referrals

Refer promptly to: 1

• Pulmonology (for fibrosis management and transplant evaluation)
• Hematology (for bone marrow surveillance and management)
• Hepatology (for liver disease monitoring)
• Medical genetics (for family counseling and cascade testing)
• Oncology (for cancer surveillance protocols)

Key Clinical Pitfalls to Avoid

• Do not dismiss normal telomere length as excluding RTEL1 pathogenicity, especially in older adults 1
• Do not delay bone marrow surveillance; baseline biopsy is essential before any abnormalities appear 6, 1
• Do not use telomere length alone for genetic counseling; it varies by specific gene and requires clinical correlation 6, 1
• Do not confuse RTEL1 with dementia-associated genes (PSEN1, PSEN2, APP, PRNP); RTEL1 does not cause neurodegeneration 4
• Do not overlook extrapulmonary manifestations that may precede or accompany lung disease 6, 7