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Hoyeraal-Hreidarsson syndrome
Disease definition
An X-linked syndromic intellectual disability considered to be a severe variant of dyskeratosis congenita characterized by intrauterine growth retardation, microcephaly, cerebellar hypoplasia, progressive combined immune deficiency and aplastic anemia.
ORPHA:3322
Classification level: Disorder- Synonym(s):
- Progressive pancytopenia-immunodeficiency-cerebellar hypoplasia syndrome
- Prevalence: <1 / 1 000 000
- Inheritance: Autosomal dominant or Autosomal recessive or X-linked recessive
- Age of onset: Infancy, Neonatal
- ICD-10: D61.0
- ICD-11: 3A70.0
- OMIM: 305000 613989 613990 615190 616353 616553
- UMLS: C1846142
- MeSH: C536068
- GARD: 346
- MedDRA: -
Summary
Epidemiology
Hoyeraal-Hreidarsson syndrome (HHS) prevalence is unknown. The syndrome may be underdiagnosed due to high mortality rates.
Clinical description
The disease generally presents in early childhood and primarily affects males. Growth retardation is usually of prenatal onset. Other clinical manifestations include 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.
Etiology
HSS is caused by mutations in the DKC1 gene (Xq28), encoding the nucleolar protein dyskerin which interacts with the human telomerase RNA complex. Mutations in other genes (TERT, RTEL1 or TINF2, ACD, PARN) involved in telomere maintenance may be associated with this disorder.
Diagnostic methods
The disorder diagnosis is based on neuroimaging. Molecular genetic testing is needed to confirm diagnosis.
Differential diagnosis
Differential diagnoses include dyskeratosis congenita, Revesz-Debuse syndrome, Pseudo-TORCH syndrome, Fanconi anemia and Nijmegen breakage syndrome.
Antenatal diagnosis
Intrauterine growth failure and cerebellar hypoplasia can be detected by prenatal imaging (ultrasounds, MRI). If the familial mutation is known, prenatal genetic testing can be proposed.
Genetic counseling
HHS follows an X-linked recessive pattern of inheritance. The disorder is very rarely inherited as an autosomal recessive form.
Management and treatment
The aplastic anemia and immunodeficiency can be treated by bone marrow transplantation. Supportive treatment for gastrointestinal complications and infections is required.
Prognosis
The prognosis is poor as the disease follows a very severe course and premature death in childhood can occur due to bone marrow failure, but survival into adulthood is possible.
A summary on this disease is available in Deutsch (2019) Español (2019) Italiano (2019) Nederlands (2019) Français (2014) Hebrew (2020, pdf)
Detailed information
Guidelines
- Clinical practice guidelines
- English (2016) - Br J Haematol
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