101 Guide to Hoyeraal Hreidarsson Syndrome

Hoyeraal Hreidarsson Syndrome: A rare genetic disorder
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Hoyeraal Hreidarsson syndrome is an extremely rare disorder. It is a multisystem genetic disorder that has X-linked recessive inheritance. It is considered a severe variant of dyskeratosis congenita. A major characteristic of the disorder is the presence of very short telomeres. To better understand the disorder, I have described all these daunting terms below.

What is a Multisystem Disorder

It refers to a disorder that affects multiple systems of the body. Hoyeraal Hreidarsson syndrome is considered as a multisystem disorder as it affects multiple systems of the body and can cause cerebellar hypoplasia, and intrauterine growth retardation.

What is a Genetic Disorder

Hoyeraal Hreidarsson syndrome is a type of genetic disorder. A genetic disorder is said to occur when there is an abnormality that occurs in the genome and causes a disease condition.

The abnormality can be due to mutations in just one gene or it can occur in more than one gene as well as due to chromosomal abnormalities. Not all mutations cause a genetic disorder. Some mutations can have a neutral while some can have a positive effect as well.

Genetic disorders that are caused by a mutation in a single gene are referred to as monogenic disorders. A lot of congenital metabolic disorders stem from mutations in a single gene. Genetic disorders that are caused by mutations in multiple genes are referred to as polygenic disorders.

Genetic disorders due to abnormalities that occur in chromosomes are called chromosomal disorders. These disorders can be caused by an extra, missing, or irregular part of a chromosome. Some examples of such disorders are Down syndrome and Turner syndrome.

There can be different types of inheritance of genetic disorders. In the case of autosomal dominant inheritance, only one copy of the gene with the mutation will cause the disorder to occur. In the case of autosomal recessive inheritance, both copies of genes with mutations are necessary for the disorder to occur.

Both, autosomal recessive and autosomal dominant disorders were caused due to mutation in the gene present in the autosomes. An example of autosomal recessive disorder is cystic fibrosis and an example of autosomal dominant disorder is Marfan syndrome.

In X-linked dominant inheritance and X -linked recessive inheritance, the mutations occur in the genes present on the X chromosome. An example of an X-linked recessive disorder is hemophilia A and an example of an X-linked dominant disorder is Aicardi syndrome.

Y-linked disorders are caused due to mutations in the genes that occur on the Y chromosome. As females do not possess a Y chromosome, they will never be affected by a Y-linked disorder. It only affects people with a Y chromosome. Thus, these disorders are passed down the generations generally from father to son. These disorders usually cause infertility.

Mitochondrial inheritance is another type of inheritance that is rare. It is also referred to as maternal inheritance. In a developing embryo, the mitochondria are provided only by the egg cell and not the sperm. Hence, only the mother passes on their mitochondrial DNA and not the father.

Any condition that is present in the mitochondrial DNA is also passed on to the child. An example of such a disorder is Leber’s hereditary optic neuropathy.

Some genetic disorders, like diabetes, occur because of a combination of mutations in the genes as well as environmental factors or lifestyle factors. These disorders are termed multifactorial disorders. The external and lifestyle factors can include exposure to a chemical, diet, and alcohol use. Another common example of this type of genetic disorder is coronary artery disease.

What is an X-linked Disorder?

Hoyeraal Hreidarsson syndrome is inherited in an X-linked recessive manner. But what does X-linked inheritance mean?

An X-linked disorder means that the genes that have the mutations are present on the X chromosome. It can be of dominant and recessive type.

In X-linked dominant disorders, the X chromosome carries the gene that is responsible for the disorder, and the gene behaves dominantly. Hence, the disorder can occur in any individual who has a copy of the affected X chromosome.

Males and females both have X chromosomes. Normally, males have one X chromosome while females have two X chromosomes. Hence, the disorder can occur in both males and females if they have a single copy of the mutated X chromosome.

In X-linked recessive disorders, the X chromosome carries the gene that is responsible for the disorder. As normally males have one X chromosome, if the gene on the X chromosome has the mutation, they will be affected by the disorder.

For these disorders to occur in females, both the X chromosomes should have the gene with mutations. In case only one X chromosome has the mutated gene, those females are called carriers. Normally, carriers do not show the phenotype of the disorder.

What is Dyskeratosis Congenita?

Hoyeraal Hreidarsson syndrome is considered to be a severe form of another rare genetic disorder called dyskeratosis congenita. It is considered to be a rare form of bone marrow failure. People who are affected by this disorder have short telomere lengths.

Almost half the people who are affected by dyskeratosis congenita have a mutation in any one of the six genes that are responsible for the production of proteins that are responsible for the maintenance of telomere function.

Three main features can be used to characterize this disorder:

  1. Nail dystrophy

The growth of nails in both fingers and toes is poor, as well as the nails have an abnormal shape, color, and texture.

  1. Reticular skin pigmentation

There are changes observed in the color of the skin, which commonly occur in the neck and chest region. The pattern that is formed by this pigmentation is lace-like or net-like.

  1. Oral leukoplakia

There are white patches that are observed in the mouth.

Patients that are suffering from this disorder have a high risk to develop some other severe or even life-threatening conditions like:

  1. Aplastic anemia

In this condition, the body does not manufacture enough blood cells.

  1. Myelodysplastic syndrome

It consists of a group of cancers where the immature blood cells that are present in the bone marrow are unable to mature or form healthy blood cells.

  1. Leukemia

It is a type of cancer that occurs in the tissues of an individual which are responsible for blood formation. The lymphatic system as well as the bone marrow are examples of these tissues.

  1. Solid tumors

It is an abnormal mass formed of tissue that is solid and does not contain any liquid or cysts. These solid tumors can be malignant or benign.

What are Telomeres?

Telomeres serve important functions by protecting the chromosome from degradation or abnormal recombination and repair etc. In most cells, the length of the telomere gets shortened with every round of cell division. Telomeres are short sequences of DNA that are repeated over and over again. Telomeres do not possess any active genes in their sequences.

Due to the end replication problem, the chromosome gets progressively shortened over multiple cell divisions. If there were important genes that were present at the end of the chromosomes, they would have been lost due to this progressive shortening of the chromosome. To protect these genes from being lost, the ends of the chromosomes have telomeres.

There is a certain limit for most cells, till which they can divide. This is because, after a certain time, the telomeres can become so short that the genes in the chromosome might also start getting deleted during cell division. Hence the cell can stop its division or undergo apoptosis.

Two important protein complexes help in the maintenance of telomeres. One is the shelterin complex and the other is the telomerase enzyme. Every time cell division occurs, the telomerase enzyme adds repeated segments of telomere DNA sequences to the end of the chromosome to maintain the telomere length.

Normally, the telomerase activity is not present in all somatic cells, but the enzyme is active in germ cells, some stem cells as well as many cancer cells.

The shelterin complex also plays an important function by protecting the telomerase, which in turn were protecting the genes in the chromosomes. The telomeres have overhangs which are single-stranded segments of DNA.

As these bases are not paired, they appear like overhangs. The DNA repair process identifies these telomeric single strands or telomeric overhangs as DNA that is damaged. Hence, the shelterin complex is important to protect telomeres from these from being recognized by the DNA repair process as damaged or abnormal DNA.

These overhangs may also base pair with double-stranded DNA strands present near it, that have a sequence that is complementary to them. This can lead to the formation of protective loops by these telomeres. It is suggested that these loops help in the prevention of chromosomes being recognized as damaged.

How is Hoyeraal Hreidarsson Syndrome Caused

It is a genetic disorder which means that it is caused by a mutation that occurs in the genes of an organism. The exact manner of the development of Hoyeraal Hreidarsson syndrome is not known currently, but it is suggested that an increased rate of telomere shortening has a role to play in the disorder.

Mutations in six genes have been associated with the Hoyeraal Hreidarsson syndrome. The genes are involved with telomere maintenance. The six genes and their functions are:

  1. DKC1– This gene can also be referred to as dyskerin pseudouridine synthase 1. The gene encodes for a protein that is called dyskerin. Dyskerin protein helps in the maintenance of telomeres. The protein also plays a part in the production of ribosomal RNA or rRNA. The protein is also called as H/ACA ribonucleoprotein complex subunit 4.
  2. TERT– This gene can also be called telomerase reverse transcriptase. The gene encodes for the catalytic subunit of the enzyme telomerase. It is responsible for catalyzing the addition, to the telomeres at the end of the chromosome, of repetitive nucleotides of the telomere sequence.
  3. RTEL1– This gene can also be called a Regulator Of Telomere Elongation Helicase 1. The gene encodes for a protein that is a DNA helicase. The protein plays an important role in the maintenance of telomeres as well as in DNA repair processes.
  4. TINF2– This gene can also be called as TERF1 interacting nuclear factor 2. The gene is responsible for encoding a protein that is a part of the shelterin complex.
  5. ACD– This gene can also be called as ACD Shelterin Complex Subunit And Telomerase Recruitment Factor. The gene is responsible for encoding a protein that plays a role in the function of the telomere. The protein plays a role in the assembly as well as stabilization of the shelterin telomere complex.
  6. PARN– This gene can also be called a poly(A)-specific ribonuclease. This gene encodes for a protein that is a 3′-exoribonuclease. The protein helps in the gene regulation process by deadenylation, through which it shortens the poly(A) mRNA tail.

Who is Affected by Hoyeraal Hreidarsson Syndrome

The disorder primarily affects males as it has an X-linked recessive inheritance. Hence males only need one mutated X chromosome to be affected by the disorder while females need both X chromosomes to be mutated for the disorder to occur.

The symptoms that are associated with Hoyeraal Hreidarsson syndrome can start to appear in newborns and infancy. The population estimate for this disorder is according to data from The United States. Below 1000 people in The United States are affected by Hoyeraal Hreidarsson syndrome.

What are the Symptoms of Hoyeraal Hreidarsson Syndrome?

Many of the symptoms of the disorder can occur in early childhood.

1. Cerebellar Hypoplasia

Cerebellar hypoplasia occurs very frequently in patients with Hoyeraal Hreidarsson syndrome. In this neurological condition, the cerebellum is abnormally small in size or underdeveloped, but the shape might be normal.

2. Immunodeficiency

Immunodeficiency occurs very frequently in patients with Hoyeraal Hreidarsson syndrome. Immunodeficiency refers to a condition where a person’s immune system does not work properly and the immune response is either reduced or is absent, and the person becomes immunocompromised.

Such an immunocompromised individual becomes prone to normal as well as opportunistic infections. The deficiency can be of various types like deficiency of T cells (T lymphocytes), and deficiency of B cells (B lymphocytes).

3. Progressive Bone Marrow Failure

In an individual with bone marrow failure, the production of blood cells is reduced and insufficient.

4. Intrauterine Growth Retardation

Intrauterine growth retardation occurs very frequently in patients with Hoyeraal Hreidarsson syndrome. It is also referred to as fetal growth restriction. In intrauterine growth retardation, the growth of the baby inside the mother’s womb is poor. The fetus is smaller in comparison to what it should be at its gestational age.

5. Microcephaly

Microcephaly occurs very frequently in patients with Hoyeraal Hreidarsson syndrome. In this condition, the head of a baby is much smaller than the normal size that is expected.

6. Aplastic Anemia

In aplastic anemia condition, the body is unable to manufacture enough blood cells.

7. Nail Dystrophy

Nail dystrophy occurs frequently in patients with Hoyeraal Hreidarsson syndrome. It can also be called Onychodystrophy. In this condition, the growth of nails in both fingers and toes is poor, and there can be abnormal changes in the texture and shape of the nail, excluding the color or nail dyschromia.

8. Dermal Atrophy

Dermal atrophy occurs very frequently in patients with Hoyeraal Hreidarsson syndrome. In this condition, atrophy of the skin occurs which can be complete or partial.

9. Intellectual Disability

Intellectual disability occurs very frequently in patients with Hoyeraal Hreidarsson syndrome. It occurs when an individual has impaired intellectual functioning as well as adaptive functioning. They face some limitations in cognitive functions and skills.

10. Oral Leukoplakia

Oral leukoplakia occurs frequently in patients with Hoyeraal Hreidarsson syndrome. In this condition, thick white patches are present inside the mouth of the affected individual.

11. Global Developmental Delay

Global developmental delay occurs frequently in patients with Hoyeraal Hreidarsson syndrome. In this condition, the physical and cognitive development of the child is delayed. The various milestones where delays can occur can be categorized as motor skills, speech, and emotional development.

12. Cerebral Calcification

Cerebral calcifications occur occasionally in patients with Hoyeraal Hreidarsson syndrome. It can also be termed intracranial calcifications. In this condition, the deposition of calcium occurs in the structures of the brain.

Some other symptoms include hyporeflexia, ventriculomegaly, premature graying of the hair, hypertonia, and excessive wrinkling of the skin.

The main reason for mortality in patients with Hoyeraal Hreidarsson syndrome is bone marrow failure. Along with the primary cause of mortality, other significant causes can be that can lead to mortality are cancer as well as pulmonary fibrosis.

How is Hoyeraal Hreidarsson Syndrome Diagnosed

  1. Neuroimaging- It includes imaging techniques to study the central nervous system. It can be used to study various aspects like structure and function. Various techniques that can be used are computer tomography, magnetic resonance imaging, and positron emission tomography. The diagnosis for imaging can be done for thin corpus callosum, cerebral calcifications, cerebellar hypoplasia, etc.
  2. Molecular genetic testing- These tests can be done for confirmation of the diagnosis.

Final Thoughts

There is supportive treatment available for the patients affected by Hoyeraal Hreidarsson syndrome. These treatments can also be referred to as symptomatic treatments as here, instead of addressing and treating the main cause of the disorder, the treatment is given to managing the symptoms.

Bone marrow transplantation can be used for the treatment of aplastic anemia and immunodeficiency. For gastrointestinal complications as well as infections, supportive treatment can be provided. Genetic counseling as well as support should be given to the patients and their families.

The affected people and their families should be made aware of all the aspects of the disorder for them to make sound decisions for the treatment of the patient. They should also be provided with resources like information related to support groups, financial support, and ongoing clinical trials.

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I am currently pursuing B. Tech in Biotechnology from Delhi Technological University, Delhi, India. My favorite subjects include Genetics, Genetic Engineering and Molecular Biology. I would one day like to go into the research field to study and find treatment for various disorders. I have written many review articles as a part of my college project related to different disorders, which help me to gain insight into the pathogenesis, diagnosis and treatments of many diseases.
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