Hoyeraal-Hreidarsson syndrome

Hoyeraal-Hreidarsson syndrome (HHS) is a severe, multisystem variant of dyskeratosis congenita, a rare inherited disorder of telomere maintenance. It was first described independently by Hoyeraal and Hreidarsson in the 1970s. HHS is characterized by intrauterine growth retardation, microcephaly, cerebellar hypoplasia, bone marrow failure, and immunodeficiency. It is considered one of the most clinically severe forms of the telomere biology disorders (telomeropathies), with critically shortened telomeres being a hallmark finding. The syndrome primarily affects the hematologic, neurological, and immune systems. Bone marrow failure typically manifests as aplastic anemia or pancytopenia, often presenting in infancy or early childhood. Immunodeficiency, particularly affecting B-cell and T-cell function, leads to increased susceptibility to severe and opportunistic infections. Neurological features include developmental delay, cerebellar hypoplasia (which may cause ataxia and coordination difficulties), and microcephaly. Some patients may also develop features of classic dyskeratosis congenita, including abnormal skin pigmentation, nail dystrophy, and oral leukoplakia, though these mucocutaneous findings may be absent or appear later in the disease course. Treatment of Hoyeraal-Hreidarsson syndrome is primarily supportive and directed at managing complications. Hematopoietic stem cell transplantation (HSCT) is the only curative option for the bone marrow failure and immunodeficiency components, though outcomes have historically been challenging due to increased sensitivity to conditioning regimens and multi-organ involvement. Reduced-intensity conditioning protocols have improved transplant outcomes in recent years. Androgens such as danazol or oxymetholone may be used to temporarily improve blood counts. Surveillance for additional complications, including pulmonary fibrosis and liver disease, is important. The prognosis remains guarded, with many patients succumbing to bone marrow failure, infections, or transplant-related complications in childhood without successful HSCT.

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