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Hoyeraal-Hreidarsson Syndrome

Last updated April 30, 2018

Approved by: Maulik P. Purohit MD, MPH

Hoyeraal-Hreidarsson Syndrome is a very rare X-linked recessive disorder characterized by intrauterine growth retardation, microcephaly, cerebellar hypoplasia, progressive combined immune deficiency and aplastic anemia.


What are the other Names for this Condition? (Also known as/Synonyms)

  • Cerebellar Hypoplasia with Pancytopenia
  • Growth Retardation Prenatal with Progressive Pancytopenia and Cerebellar Hypoplasia
  • HHS (Hoyeraal-Hreidarsson Syndrome)

What is Hoyeraal-Hreidarsson Syndrome? (Definition/Background Information)

  • Hoyeraal-Hreidarsson Syndrome (HHS) is a very rare X-linked recessive disorder considered to be a severe variant of dyskeratosis congenita characterized by intrauterine growth retardation, microcephaly, cerebellar hypoplasia, progressive combined immune deficiency and aplastic anemia
  • 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
  • Differential diagnoses include dyskeratosis congenita, Revesz-Debuse syndrome, Pseudo-TORCH syndrome, Fanconi anemia and Nijmegen breakage syndrome
  • 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. More than 12 patients have been reported to date but the syndrome may be underdiagnosed due to high mortality rates

(Source: Hoyeraal Hreidarsson Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Who gets Hoyeraal-Hreidarsson Syndrome? (Age and Sex Distribution)

  • Hoyeraal-Hreidarsson Syndrome is an extremely rare congenital disorder that is reported in less than 20 individuals
  • The presentation of symptoms may occur at birth
  • Typically, only males are affected, since HHS is an X-linked condition
  • Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Hoyeraal-Hreidarsson Syndrome? (Predisposing Factors)

  • A positive family history may be an important risk factor, since Hoyeraal-Hreidarsson Syndrome can be inherited
  • Currently, no other risk factors have been clearly identified for HHS

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Hoyeraal-Hreidarsson Syndrome? (Etiology)

  • Hoyeraal-Hreidarsson Syndrome is caused by mutations in the DCK1 gene (Xq28), encoding the nucleolar proteindyskerin 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)
  • HHS follows an X-linked recessive pattern of inheritance

(Source: Hoyeraal Hreidarsson Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

X-linked recessive pattern of inheritance: The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

What are the Signs and Symptoms of Hoyeraal-Hreidarsson Syndrome?

The signs and symptoms of Hoyeraal-Hreidarsson Syndrome may include:

Very frequently present symptoms in 80-99% of the cases:

  • Cerebellar hypoplasia
  • Dermal atrophy
  • Immunodeficiency
  • Intellectual disability
  • Intrauterine growth retardation
  • Microcephaly
  • Thrombocytopenia

Frequently present symptoms in 30-79% of the cases:

  • Abnormality of coagulation
  • Anemia
  • Cerebral cortical atrophy
  • Excessive wrinkled skin
  • Generalized hyperpigmentation
  • Generalized hypopigmentation of hair
  • Hypertonia
  • Nail dystrophy
  • Oral leukoplakia
  • Premature graying of hair
  • Sparse scalp hair
  • Ventriculomegaly

Occasionally present symptoms in 5-29% of the cases:

  • Abnormality of leukocytes
  • Ataxia
  • Bone marrow hypocellularity
  • Cerebral calcification
  • Hyporeflexia
  • Neoplasm

(Source: Hoyeraal Hreidarsson Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Hoyeraal-Hreidarsson Syndrome Diagnosed?

The diagnosis of Hoyeraal-Hreidarsson Syndrome may involve:

  • Cerebellar hypoplasia/atrophy, small brainstem, thin corpus callosum and cerebral calcifications have been reported on neuroimaging
  • Intrauterine growth failure and cerebellar hypoplasia can be detected by prenatal ultrasounds
  • 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

(Source: Hoyeraal Hreidarsson Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Hoyeraal-Hreidarsson Syndrome?

The complications of Hoyeraal-Hreidarsson Syndrome may include:

  • Failure to thrive
  • Severe neurological abnormalities
  • Development of cancer, in some cases

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Hoyeraal-Hreidarsson Syndrome Treated?

The treatment of Hoyeraal-Hreidarsson Syndrome may involve:

  • The aplastic anemia and immunodeficiency can be treated by bone marrow transplantation
  • Supportive treatment for gastrointestinal complications and infections is required

(Source: Hoyeraal Hreidarsson Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

How can Hoyeraal-Hreidarsson Syndrome be Prevented?

Hoyeraal Hreidarsson Syndrome may not be preventable, since it is a genetic disorder

  • Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
  • If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
  • Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended

What is the Prognosis of Hoyeraal-Hreidarsson Syndrome? (Outcomes/Resolutions)

  • The prognosis of Hoyeraal Hreidarsson Syndrome is poor as the disease follows a very severe course and premature death in childhood can occur due to bone marrow failure

(Source: Hoyeraal Hreidarsson Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Additional and Relevant Useful Information for Hoyeraal-Hreidarsson Syndrome:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/

What are some Useful Resources for Additional Information?


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Reviewed and Approved by a member of the DoveMed Editorial Board
First uploaded: April 30, 2018
Last updated: April 30, 2018