Dyskeratosis congenita

Dyskeratosis congenita
ICD-10	Q82.8
ICD-9	757.39
OMIM	305000
DiseasesDB	30105
eMedicine	derm/
MeSH	D019871

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]

Overview

Dyskeratosis congenita (DKC), also called Zinsser-Cole-Engman syndrome, is a rare progressive congenital disorder that in some ways resembles premature aging (similar to progeria). The disease mainly affects the integumentary system, the organ system that protects the body from damage, with a major consequence being anomalies of the bone marrow.

Pathophysiology

Though the exact pathology of the disease is not yet fully understood, most evidence points to dyskeratosis congenita being primarily a disorder of poor telomere maintenance. Specifically, the disease is related to one or more mutations which directly or indirectly affect the vertebrate telomerase RNA component (TERC).

Telomerase is a reverse transcriptase which maintains a specific repeat sequence of DNA, the telomere, during development. Telomeres are placed by telomerase on both ends of linear chromosomes as a way to protect linear DNA from general forms of chemical damage and to correct for the chromosomal end-shortening that occurs during normal DNA replication. This end-shortening is the result of the eukaryotic DNA polymerases having no mechanism for synthesizing the final nucleotides present on the end of the "lagging strand" of double stranded DNA. DNA polymerase can only synthesize new DNA from an old DNA strand in the 5'->3' direction. Given that DNA has two strands that are complementary, one strand must be 5'->3' while the other is 3'->5'. This inability to synthesize in the 3'->5' directionality is compensated with the use of Okazaki fragments, short pieces of DNA that are synthesized 5'->3' from the 3'->5' as the replication fork moves. As DNA polymerase requires RNA primers for DNA binding in order to commence replication, each Okazaki fragment is thus preceded by an RNA primer on the strand being synthesized. When the end of the chromosome is reached, the final RNA primer is placed upon this nucleotide region, and it is inevitably removed. Unfortunately once the primer is removed, DNA polymerase is unable to synthesize the remaining bases.

Sufferers of DKC have been shown to have a reduction in TERC levels invariably affecting the normal function of telomerase which maintains these telomeres. With TERC levels down, telomere maintenance during development suffers accordingly. In humans, telomerase is inactive in most cell types after early development (except in extreme cases such as cancer). Thus, if telomerase is not able to efficiently affect the DNA in the beginning of life, chromosomal instability becomes a grave possibility in individuals much earlier than would be expected.

A study shows that proliferative defects in DC skin keratinocytes are corrected by expression of the telomerase reverse transcriptase, TERT, or by activation of endogenous telomerase through expression of papillomavirus E6/E7 or the telomerase RNA component, TERC. Experimental Dermatology 2010; 19: 279–288

Genetics

Of the components of the telomerase RNA component (TERC), one of key importance is the box H/ACA domain. This H/ACA domain is responsible for maturation and stability of TERC and therefore of telomerase as a whole. The mammalian H/ACA ribonucleoprotein contains four protein subunits: dyskerin, Gar1, Nop10, and Nhp2. Mutations in Nop10, Nhp2 and dyskerin1 have all been shown to lead to DKC-like symptoms.

Autosomal recessive form

The true phenotype of DKC individuals may depend upon which protein has incurred a mutation. One documented autosomal recessive mutation in a family that carries DKC has been found in Nop10. Specifically, the mutation is a change of base from cytosine to thymine in a highly conserved region of the Nop10 sequence. This mutation, on chromosome 15, results in an amino acid change from arginine to tryptophan. Homozygous recessive individuals show the symptoms of dyskeratosis congenita in full. As compared to age-matched normal individuals, those suffering from DKC have telomeres of a much shorter length. Furthermore, heterozygotes, those who have one normal allele and one coding for the disease, also show relatively shortened telomeres. The cause of this was determined to be a reduction in TERC levels in those with the Nop10 mutation. With TERC levels down, telomere maintenance, especially in development, would be presumed to suffer accordingly. This would lead to the telomere shortening described.

Nhp2 mutations are similar in characterization to Nop10. These mutations are also autosomal recessive with three specific single-nucleotide polymorphisms being recognized which result in dyskeratosis congenita. Also like Nop10, individuals with these Nhp2 mutations have a reduction in the amount of telomerase RNA component (TERC) present in the cell. Again it can be presumed that a reduction in TERC results in aberrant telomere maintenance and thus shortened telomeres. Those homozygous recessive for mutations in Nhp2 do show shorter telomeres when compared with age-matched normal individuals.

X-linked form

The best characterized form of dyskeratosis congenita is a result of one or more mutations in the long arm of the X chromosome in the gene DKC1. This results in the X-linked recessive form of the disease wherein the major protein affected is dyskerin. Of the five mutations described by Heiss and colleagues in Nature Genetics, four were single nucleotide polymorphisms all resulting in the change of highly conserved amino acids. One case was an in-frame deletion resulting in the loss of a leucine residue, also conserved in mammals. In three of the cases, the specific amino acids affected (phenylalanine, proline, glycine) are found in the same locus in humans as they are in yeast (S. Cerevisiae) and the brown rat (R. Norvegicus). This establishes the sequence conservation and importance of dyskerin within the eukaryotes. The relevant nature of dyskerin throughout most species is to catalyze the post-transcriptional pseudouridylation of specific uridines found in non-coding RNAs, such as ribosomal RNA (rRNA). Cbf5, the yeast analog of human dyskerin, is indeed known to be associated with the processing and maturation of rRNA. In humans this role can be attributed to dyskerin. Thus, the X-linked form of this disease may result in specific issues related to dysfunctional rRNA and perhaps a graver phenotype. Within the vertebrates, as opposed to single celled eukaryotes, dyskerin is a key component of the telomerase RNA component (TERC) in the form of the H/ACA motif. This X-linked variety, like the Nop10 and Nhp2 mutations, demonstrates shortened telomeres as a result of lower TERC concentrations.

Autosomal dominant form

The evidence supporting the importance of the H/ACA domain in human telomerase is abundant. At least one study has shown that these mutations affect telomerase activity by negatively affecting pre-RNP assembly and maturation of human telomerase RNA. Nonetheless, mutations which directly affect the telomerase RNA components would presumably exist and should also cause premature aging or DKC-like symptoms. Indeed, three families with mutations in the human TERC gene have been studied with intriguing results. In two of these families, two family-specific single nucleotide polymorphisms were present while in the other there persisted a large-scale deletion (821 base pairs of DNA) on chromosome 3 which includes 74 bases coding for a section of the H/ACA domain. These three different mutations result in a mild form of dyskeratosis congenita which uniquely follows an autosomal dominant pattern of inheritance. Premature graying, early dental loss, predisposition to skin cancer, as well as shortening of telomere length continue to be characteristic of this disease.

Epidemiology and Demographics

Age: The mucocutaneous features of DKC typically develop between ages 5 and 15 years. The median age of onset of the peripheral cytopenia is 10 years.

Gender: The male-to-female ratio is approximately 3:1.

Natural history, Complications and Prognosis

Prognosis of the disease is poor with a mean survival of 30 years. Prognosis is worse for X-linked and autosomal recessive forms compared to autosomal dominant form.

Complications include:

• Conjunctivitis, blepharitides, lacrimal duct stenosis, and pterygium
• Mandibular hypoplasia, osteoporosis, avascular necrosis, and scoliosis.
• Cirrhosis
• Bone marrow failure - infections, bleeding
• Pulmonary fibrosis
• Dysphagia, dysuria, phimosis, and epiphora - due to constriction and stenosis can occur at the sites of leukoplakia
• Increased risk of malignancy - increased prevalence of malignant mucosal neoplasms, particularly squamous cell carcinoma of the mouth, nasopharynx, esophagus, rectum, vagina, or cervix. These often occur within sites of leukoplakia. The prevalence of squamous cell carcinoma of the skin is also increased.
• Death - due to infections, bleeding

Diagnosis

Symptoms

Patients with DKC complain of

• Cutaneous pigmentation - hyper or hypo-pigmentation
• Premature graying of hair
• Dystrophy of the nails - ridging and longitudinal splitting
• Leukoplakia of the oral mucosa (patches on the tongue and inside the mouth)
• Continuous/excess lacrimation (due to atresia of the lacrimal ducts)
• Decreased libido (due to testicular atrophy in the male carriers).

Physical Examination

The triad of reticulated hyperpigmentation of the skin, nail dystrophy, and leukoplakia characterizes DKC. The syndrome is clinically heterogeneous; in addition to the diagnostic mucocutaneous features and bone marrow failure, affected individuals can have a variety of other clinical features.

Skin:

• Abnormal skin pigmentation - tan-to-gray hyperpigmented or hypopigmented macules and patches in a mottled or reticulated pattern. Reticulated pigmentation occurs in approximately 90% of patients.
• Poikilodermatous changes with atrophy and telangiectasia are common.
• Alopecia of the scalp, eyebrows, and eyelashes
• Premature graying of the hair
• Hyperhidrosis
• Hyperkeratosis of the palms and soles
• Adermatoglyphia (loss of dermal ridges on fingers and toes).

The cutaneous presentation may clinically and histologically resemble graft versus host disease. The typical distribution involves the sun-exposed areas, including the upper trunk, neck, and face.

Extremities:

• Nail dystrophy (ridging and longitudinal splitting) - seen in approximately 90% of patients, with fingernail involvement often preceding toenail involvement.
• Absent nails - in advanced disease.

Mucosal findings:

• Mucosal leukoplakia - occurs in approximately 80% of patients and typically involves the buccal mucosa, tongue, and oropharynx.

Patients also may have an increased prevalence and severity of periodontal disease. Other mucosal sites may be involved (e.g., esophagus, urethral meatus, glans penis, lacrimal duct, conjunctiva, vagina, anus).

Respiratory:

• Rales are heard in those having pulmonary fibrosis.

Neurologic:

• Low ID
• Patients may have learning difficulties and mental retardation.

Eye:

• Excessive tearing
• Red eyes

Abdomen:

• Esophageal webs
• Hepatosplenomegaly

Genitourinary system findings::

• Hypospastic testes (small testis),
• Hypospadias
• Ureteral stenosis

Female carriers:

Female carries of DKC may have subtle clinical features. One study showed that 3 of 20 female carriers had clinical features that included a single dystrophic nail, a patch of hypopigmentation, or mild leukoplakia.

Predisposition to cancer

Susceptibility to cancer seems counterintuitive because in many known cancers reactivation of telomerase is actually a required step for malignancy to evolve (See discussion here). In a disease where telomerase is affected, it does not seem to follow that cancer would be a complication to result. The authors note the paradoxical nature of cancer predisposition in individuals who seem to lack one of the required components for cancerous lesions. It is discussed that with reduced telomeres, chromosomes will likely be attached together at their ends through the non-homologous end joining pathway (NHEJ). If this were a common enough occurrence, malignancy even without functional telomerase seems probable.

Treatment

Recent research has used Induced pluripotent stem cells to study the disease mechanisms in humans, and discovered that the repgrogramming of somatic cells restores telomere elongation in dyskeratosis congenita cells despite the genetic lesions that affect telomerase. The reprogrammed DC cells were able to overcome a critical limitation in TERC levels and restored function (telomere maintenance and self-renewal). Therapeutically, methods aimed at increasing TERC expression could prove beneficial in DC patients.

See also

• Cutaneous conditions
• List of cutaneous conditions

External links

• GeneReviews/NCBI/NIH/UW entry on Dyskeratosis Congenita
• Dyskeratosis Congenita research study of Inherited Bone Marrow Failure Syndromes (IBMFS)