Hoyeraal-Hreidarsson syndrome (HHS) is a very rare X-linked recessive disorder considered to be a severe variant of dyskeratosis congenita (see this term) characterized by intrauterine growth retardation, microcephaly, cerebellar hypoplasia, progressive combined immune deficiency and aplastic anemia.
Prevalence and incidence are unknown. More than 12 patients have been reported to date but the syndrome may be underdiagnosed due to high mortality rates.
The disease generally presents in early childhood and primarily affects males. Growth retardation is usually of prenatal onset. Other clinical manifestations include intellectual disability, microcephaly, mucocutaneous lesions (hyperpigmentation, nail dystrophy, premalignant leukoplakia affecting oral and gastrointestinal mucosa), early onset bone marrow failure, immunodeficiency and pancytopenia. Cancer predisposition is also reported.
HSS is caused by mutations in the DCK1 gene (Xq28), encoding the nucleolar protein dyskerin which interacts with the human telomerase RNA complex. Mutations in other genes involved in telomere maintenance may be associated with this disorder (TERT, RTEL1 or TINF2).
Cerebellar hypoplasia/atrophy, small brainstem, thin corpus callosum and cerebral calcifications have been reported on neuroimaging. Molecular genetic testing is needed to confirm diagnosis.
Differential diagnoses include dyskeratosis congenita, Revesz-Debuse syndrome, Pseudo-TORCH syndrome, Fanconi anemia and Nijmegen breakage syndrome (see these terms).
Intrauterine growth failure and cerebellar hypoplasia can be detected by prenatal ultrasounds. If the familial mutation is known, prenatal genetic testing can be proposed.
HHS follows an X-linked recessive pattern of inheritance.
The aplastic anemia and immunodeficiency can be treated by bone marrow transplantation. Supportive treatment for gastrointestinal complications and infections is required.
The prognosis is poor as the disease follows a very severe course and premature death in childhood can occur due to bone marrow failure.
Last update: February 2013