RTEL1-related disorders

What are RTEL1-related Disorders?

Harmful genetic changes (mutations) in the RTEL1 gene are associated with two disorders called Hoyeraal-Hreidarsson syndrome (HHS) and dyskeratosis congenita (DKC). These inherited disorders impair the proper maintenance of chromosome ends (telomeres) and DNA repair, leading to a wide variety of symptoms. Most patients with mutations in the RTEL1 gene present with HHS.

Hoyeraal-Hreidarsson Syndrome

HHS is associated with growth restriction in utero and after birth, small head size (microcephaly), a small or missing part of the brain that coordinates movement (cerebellum), severe developmental delay, and immunodeficiency as a result of bone-marrow failure. Most individuals with HHS die in childhood as a result of these symptoms.

Dyskeratosis Congenita

DKC is clinically less severe than HHS and is characterized by three main symptoms: abnormal skin coloring, specifically in the upper body; white patches on the tongue and inside of the mouth (leukoplakia); and abnormal nails of the fingers and toes (nail dystrophy). Other symptoms of DKC include short stature, dental abnormalities, thick scarring (fibrosis) in the lungs and liver, narrowing of the muscular tube connecting the throat with the stomach (esophagus), narrowing of the tube connecting the urinary bladder to the urinary opening for the removal of urine (urethra, typically only in males), weak or brittle bones (osteoporosis), progressive bone-marrow failure, and cancer (most commonly leukemia). Progressive bone-marrow failure and cancer are the most common causes of death. Most individuals with DKC have normal intelligence and development, but there are reports of individuals who are more severely affected who have varying degrees of intellectual disability or developmental delay. These symptoms are variable, as not all individuals with DKC will have the same presentation. Harmful genetic changes in RTEL1 make up to 2-8% of all cases of DKC.

How common are RTEL1-related Disorders?

The worldwide frequency of RTEL1-related disorders in the general population is not known. RTEL1-related disorders are estimated to affect about 1 in 1,000,000 individuals. A founder effect (high frequency of disease because the group arose from a small, possibly isolated population) has been described in the Ashkenazi Jewish population, and incidence of RTEL1-related disorders may therefore be higher in this population.

How are RTEL1-related Disorders treated?

There is no cure for RTEL1-related disorders. Regular screening for bone-marrow failure and leukemia is recommended, with hematopoietic stem-cell transplantation used as a treatment option if needed. Annual pulmonary-function tests to assess for fibrosis as well as periodic follow-up with a multidisciplinary team of specialists are recommended to assess for other symptom development.

What is the prognosis for an individual with an RTEL1-related Disorder?

The prognosis for an individual with HHS is typically poor, as it often leads to early bone-marrow failure and premature death in childhood. The prognosis for an individual with DKC is variable and is dependent on the severity. Some individuals with DKC live into adulthood, while some die in childhood as a result of bone-marrow failure, lung complications, or cancer.

Additional considerations for carriers

Carriers of RTEL1-related disorders may or may not show symptoms of disease as they age. While the specific risk in carriers is uncertain, recent studies have shown that carriers of RTEL1-related disorders may be at risk of developing familial interstitial pneumonia, idiopathic pulmonary fibrosis, myelodysplastic syndrome, or other symptoms at older ages.