Hoyeraal–Hreidarsson syndrome explained

Hoyeraal–Hreidarsson syndrome
Synonyms:	Progressive pancytopenia-immunodeficiency-cerebellar hypoplasia syndrome^[1]
Causes:	Mutation in genes related to telomere maintenance

Hoyeraal–Hreidasson syndrome is a very rare multisystem X-linked recessive disorder characterized by excessively short telomeres and is considered a severe form of dyskeratosis congenita.^{[2] [3]} Being an X-linked disorder, Hoyeraal–Hreidasson syndrome primarily affects males. Patients typically present in early childhood with cerebellar hypoplasia, immunodeficiency, progressive bone marrow failure, and intrauterine growth restriction. The primary cause of death in Hoyeraal–Hreidasson syndrome is bone marrow failure, but mortality from cancer and pulmonary fibrosis is also significant.^{[4] [5] [6]}

Presentation

The currently recognized features are cerebellar hypoplasia, immunodeficiency, progressive bone marrow failure, and intrauterine growth restriction. Patients also commonly exhibit symptoms such as microcephaly, aplastic anemia, and intellectual disability.

Overlap with dyskeratosis congenita

Patients with Hoyeraal–Hreidasson syndrome frequently present with the mucocutaneous triad of nail dysplasia, lacy skin pigmentation, and oral leukoplakia.

Pathogenesis

Although the pathogenesis remains unknown, it is strongly suspected that the clinical sequelae of Hoyeraal–Hreidasson syndrome arise from the accelerated telomere shortening. It has been associated with mutations in DKC1, TERT, RTEL1, TINF2, ACD, and PARN.^{[7] [8]}

Diagnosis

• Neuroimaging cerebellar hypoplasia/atrophy, small brainstem, thin corpus callosum and cerebral calcifications
• Molecular genetic testing for confirmation

Treatment

Current treatment is supportive:

• The aplastic anemia and immunodeficiency can be treated by bone marrow transplantation.
• Supportive treatment for gastrointestinal complications and infections.
• Genetic counselling.

See also

• Dyskeratosis congenita

External links

• Hoyeraal–Hreidarsson syndrome on Orphanet

Notes and References

1. Web site: Orphanet: Hoyeraal Hreidarsson syndrome . www.orpha.net . 15 June 2019 . en.
2. Glousker G, Touzot F, Revy P, Tzfati Y, Savage SA . Unraveling the pathogenesis of Hoyeraal–Hreidarsson syndrome, a complex telomere biology disorder . British Journal of Haematology . 170 . 4 . 457–71 . August 2015 . 25940403 . 4526362 . 10.1111/bjh.13442 .
3. Knight SW, Heiss NS, Vulliamy TJ, Aalfs CM, McMahon C, Richmond P, Jones A, Hennekam RC, Poustka A, Mason PJ, Dokal I . 6 . Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal–Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1 . British Journal of Haematology . 107 . 2 . 335–9 . November 1999 . 10583221 . 10.1046/j.1365-2141.1999.01690.x . 23750791 .
4. Deng Z, Glousker G, Molczan A, Fox AJ, Lamm N, Dheekollu J, Weizman OE, Schertzer M, Wang Z, Vladimirova O, Schug J, Aker M, Londoño-Vallejo A, Kaestner KH, Lieberman PM, Tzfati Y . 6 . Inherited mutations in the helicase RTEL1 cause telomere dysfunction and Hoyeraal–Hreidarsson syndrome . Proceedings of the National Academy of Sciences of the United States of America . 110 . 36 . E3408-16 . September 2013 . 23959892 . 3767560 . 10.1073/pnas.1300600110 . 2013PNAS..110E3408D . free .
5. Le Guen T, Jullien L, Touzot F, Schertzer M, Gaillard L, Perderiset M, Carpentier W, Nitschke P, Picard C, Couillault G, Soulier J, Fischer A, Callebaut I, Jabado N, Londono-Vallejo A, de Villartay JP, Revy P . 6 . Human RTEL1 deficiency causes Hoyeraal–Hreidarsson syndrome with short telomeres and genome instability . Human Molecular Genetics . 22 . 16 . 3239–49 . August 2013 . 23591994 . 10.1093/hmg/ddt178 . free .
6. Jullien L, Kannengiesser C, Kermasson L, Cormier-Daire V, Leblanc T, Soulier J, Londono-Vallejo A, de Villartay JP, Callebaut I, Revy P . Mutations of the RTEL1 Helicase in a Hoyeraal–Hreidarsson Syndrome Patient Highlight the Importance of the ARCH Domain . Human Mutation . 37 . 5 . 469–72 . May 2016 . 26847928 . 10.1002/humu.22966 . 21314739 . free .
7. Benyelles M, Episkopou H, O'Donohue MF, Kermasson L, Frange P, Poulain F, Burcu Belen F, Polat M, Bole-Feysot C, Langa-Vives F, Gleizes PE, de Villartay JP, Callebaut I, Decottignies A, Revy P . Impaired telomere integrity and rRNA biogenesis in PARN-deficient patients and knock-out models . EMBO Molecular Medicine . 11 . 7 . e10201 . July 2019 . 31273937 . 6609912 . 10.15252/emmm.201810201 .
8. Web site: Hoyeraal Hreidarsson syndrome . Genetic and Rare Diseases Information Center . National Institutes of Health . 1 August 2019 . 2021-11-01.