Dyskeratosis Congenita -Clinical Features, Investigation, Diagnosis

It is a group of inherited disorders characterized by progressive, rapid telomere shortening and clinically manifesting with dermatological manifestation and BMFS. Genes commonly implicated

• Most common: DKC-1: Xp28 codes for the protein Dyskerin (20-30%) - XLR inheritance
• TINF- 2 gene 2^nd most common (12-20%) - AD inheritance
• TERC gene (10%) - AD inheritance
• TERT gene - AD or AR inheritance
• RTEL-1 gene - AD or AR inheritance
• CTC-1 gene - AR inheritance

Pediatric Hematology

At the end of chromosomes there are non-coding regions known as telomeres. Telomeres are rich in guanine residues. As cells divide the telomere length goes on progressively decreasing. If the critical length is decreased with each cell cycle. There is a time when the cell undergoes apoptosis and eventually dies. In the case of stem cells as well as hematopoietic cells or germ cells, there is an enzyme called telomerase, it keeps the length of the telomere intact that's why they continue to remain active and keep dividing.

If the telomerase enzyme won't function these cells gradually will get smaller and will not function properly. Mutation in one or more genes involved in telomere lengthening which leads to progressive and rapid telomere shortening. Especially in hematopoietic stem cells and once telomeres shorten beyond a certain point it leads to apoptosis of HPC leading to BM failure syndrome.

Time of onset of manifestations 

• Within 1st decade of life DKC-1, TINF-2 present
• TERT, TERC present after 1st decade of life
• In classic DKC, usually the skin manifestation appear earlier

Clinical Features

A. Skin Manifestations

• Classic triad includes
  • Dysplastic nails-87-88%
  • Lacy reticular pigmentation of upper chest/neck (most Common) -89%
  • Oral leukoplakia-70%
• In all individuals this triad will not be present, dysplastic nails and lacy reticular pigmentation these symptoms start in the 1st decade of life and oral leukoplakia in later life.

B. Bone Marrow Failure

• Usually develops within the 1st 2 decades. 80% of the patients develop BM failure by age 30 years. Almost 90% of the patients have BM failure at some points in their life. Initially thrombocytopenia or anemia or both, Later develop full-blown pancytopenia.

C. Others

• Ocular: Epiphora in 30% (NLD obstruction), conjunctivitis, strabismus, cataracts
• CNS: Developmental delay and learning difficulties in 25%
• Skeletal: Osteoporosis, AVN scoliosis, mandibular hypoplasia
• Genitourinary: Hypospadias, hypoplastic testis, horseshoe kidneys
• GIT: In 10% cases, peptic ulcers, bleeding, fibrosis, and hepatomegaly
• Immune abnormalities: With low Ig and low B/T cell counts. In DKC-1 type

Investigation

• Blood investigation
  • Pancytopenia found in later stages and there may be bi-cytopenia in earlier stages
  • There will be macrocytic RBCs and there will be an increase in HbF level
• BM studies - Hypocellular BM.
• Investigation of choice in these children are for circulating lymphocytes.
  • They will show a normal chromosomal fragility.
  • There will be no increase in fragility.
• When the FISH examination is performed, there will be severe telomere shortening below 1st centile of normal.
• Cultured fibroblasts has an increase in the tendency for chromosomal rearrangements - this will be unrelated to DEB or MMC

Diagnosis

• Clinical diagnosis of classic DKC. 2 out of 4 should be present:
  • Dystrophic nails
  • Reticular hyperpigmentation
  • Oral leukoplakia
  • BM failure
• Any 2 out of these 4 + Any 2 of the somatic abnormalities described for DKC
• Confirm by FISH analysis >97% sensitivity and 91% specificity

Complications

• Malignancies develop in 10-15% by 3rd or 4th decade of life
  • 40% of the squamous cell of head and neck
  • Squamous carcinoma cell of esophagus
  • There can also be adenocarcinoma of colorectal region
  • There can be AML and MDS.
• Pulmonary fibrosis can be seen
• Hepatic fibrosis can also be found here
• Severe GIT bleeding would be present

Treatment

• Transfusion can be done
• Androgens are effective up to 70% in these individuals. Response decreases as age advances.
• HSCT which is curative therapy but has a higher complication rate than FA.
• G-CSF injection but there is a risk of progression to AML or MDS.

Extra-Edge POINTS 

• Variants of DC more than severe than normal classic disease
• Hoyeraal-Hreidarsson syndrome: DC + cerebellar hypoplasia. Seen due to DKC-1 mutation
• Revesz syndrome: DC + bilateral exudative retinopathy. TINF2 gene mutation. 20% of them can have CNS calcifications.
• Coats plus syndrome: DC + retinal telangiectasia and exudates + portal HTN due to vascular ectasias. CTC-1 gene mutations. 25% of them can have additional CNS calcifications.
• Nelson says………

The mortality rate associated with HSCT is higher in DC than that observed with other 

IBMFSs and likely caused by the high level of pulmonary vascular complications seen in 

the patients with DC that are related to the underlying telomere maintenance defects. 

The major cause of death is BM failure, followed by complications of HSCT, cancers, fatal pulmonary problems, and GIT bleeding. Median survival age in children is 30 yrs.

Hope you found this blog helpful for your E-learning for NEET SS Pediatrics. For more informative and interesting posts like these, keep reading PrepLadder’s blogs. 

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