Dyskeratosis congenita (DC) is a clinically and genetically heterogeneous multisystem inherited syndrome caused by mutations in genes that encode the protein components of the telomerase complex and shelterin complex. DC is a rare disease with an estimated annual incidence of 1 in 1,000,000 [1]. Genotype–phenotype correlations are complex due to a variety of gene mutations, disease anticipation, and genetic and environmental modifier effects. The classical clinical form of the disease is characterized by the mucocutaneous triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia [2, 3]. The abnormal skin pigmentation and nail changes usually appear first, often under 10 years of age. Additional features of the clinical presentation include BMF, myelodysplastic syndrome (MDS), epiphora, blepharitis, premature graining, alopecia, growth retardation, cerebellar hypoplasia and microcephaly, esophageal stenosis, urethral stenosis, liver disease, pulmonary fibrosis, and avascular necrosis of the hips or shoulders. DC patients have an increased risk of developing malignant disease [4, 5]. Bone marrow failure is considered to be an important and major complication of DC, and is a leading cause of death that develops in around 85% of cases. DC is caused by mutations in genes that encode protein components of the telomerase complex and shelterin complex. Since 1998 at least 14 DC genes involved in the telomere's shortening have been identified, accounting for approximately 70–80% of DC cases [6,7,8]. These genes encode proteins for the maintenance of telomeres, which are located at the ends of chromosomes. DC can be inherited in an X-linked, autosomal dominant (AD), or autosomal recessive (AR) pattern. Mutations in
A 19-month-old boy was referred to the hematology department at the University clinic for children's diseases in order to evaluate the possibility of thrombocytopenia. He is of Albanian ancestry, born after a normal pregnancy from healthy parents. There is no consanguinity in the family. Clinical examination at admission revealed pallor, cutaneous and mucosal hemorrhagic syndrome. He had growth retardation below the third percentile on the growth curve. Laboratory tests have shown thrombocytopenia (with PLT 27 × 109/l), with macrocytic anemia (Hb: 102 g/L, RBC 3.3 × 109/l, MCV: 98.2 fL) and WBC: 6.03 × 109/l, neutrophil count of 1.25 109/l. BM analysis showed megaloblastic maturation in BM with megakaryocyte hypoplasia. Chromosome analysis indicated no numerical or structural chromosomal abnormalities. The following month, the PLT number decreased to 7 × 109/l with the development of severe macrocytic anemia (Hb 72g/L; RBC 2.3 ×109/l). Blood counts deteriorated with the development of pancytopenia and aplastic anemia. Four months later, a physical examination revealed nail dystrophy and skin pigmentation involving the neck. Differential diagnosis suggested Fancony anemia or DC. The diagnosis of DC was established with the identification of a known pathogenic
Hematology results and clinical characteristic during the follow up
Hb (g/l) | 102 | 86 | 72 |
RBC (109/l) | 3.3 | 2.6 | 2.3 |
MCV (fl) | 98.2 | 102 | 105 |
WBC (109/l) | 6.03 | 4.8 | 4.9 |
Granulocyte (109/l) | 1.25 | 1.0 | 0.8 |
PLT (109/l) | 27 | 12 | 7 |
BM aspiration and BM biopsy | Megaloblastic maturation, Megakaryocytic hypoplasia | Hypo plastic, fatty bone marrow | |
Nail dystrophy | No | No | Present |
Skin hyperpigmentation | No | No | Present |
Mucosal Leucoplakia | No | No | No |
Genetic analyses | c.845G>A, p. (Arg282His) |
We performed clinical exome sequencing on a MiSeq desktop sequencer, using TruSight One kit (Illumina) for the proband. The analysis revealed the presence of the known pathogenic variant c.845G>A, p.(Arg282His), in a heterozygous state, in the
The medical management of each DC patient is very complex and should take into consideration the patient's specific needs. Patients with DC and BMF do not respond to immunosuppressive therapy, and allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for BMF. Our patient received corticosteroids for one month without any response to the therapy. After the confirmation of DC, HSCT was performed by an unrelated full matched donor. The patient experienced engraftment failure and underwent a second unrelated HSCT. One year after the second HSCT he was in a good clinical condition. Once the bone marrow failure issue was resolved, thrombocytes were around 30–40 × 109/l and the boy had a relatively good quality of life.
We report the clinical, laboratory and genetic findings of a 19-month-old Albanian boy from North Macedonia with aplastic anemia as a first clinical presentation of DC. A known pathogenic missense variant, c.845G>A, p.(Arg282His), located in exon 6 of the
Autosomal dominant DC is a clinically and genetically heterogeneous group of the disease. To date, heterozygous variants in 4 genes (
List of known pathogenic
chr14:24711458 | c.81C>A | p.Cys27Ter | rs1060499576 | DC, RS | / |
chr14:24709890 | c.796C>T | p.Arg266Ter | rs1064795632 | N/A | / |
chr14:24709881 | c.805C>T | p.Gln269Ter | rs387907153 | DC, mucocutaneous features, BMF | 19, 18 |
chr14:24709875 | c.811C>T | p.Gln271Ter | rs387907154 | AA | 19 |
chr14:24709860 | c.826delA | p.Arg276GlyfsTer41 | rs863223324 | ND, BMF, lichenoid tongue, dry skin, intrauterine growth retardation | 18 |
chr14:24709848 | c.838A>T | p.Lys280Ter | rs121918543 | DC, HHS, and RS | 12, 15 |
chr14:24709848 | c.838A>G | p.Lys280Glu | rs121918543 | DC | 12, 21, 8 |
chr14:24709847 | c.839delA | p.Lys280ArgfsTer37 | rs1594551449 | DC, RS | 19 |
chr14:24709842 | c.844C>A | p.Arg282Ser | rs121918545 | DC, RS | 12, 17, 23 |
chr14:24709842 | c.844C>T | p.Arg282Cys | rs121918545 | DC, AA, PD and mucosal changes | 20, 12, 17 |
chr14:24709841 | c.845G>A | p.Arg282His | rs121918544 | DC, HHS, RS | 12, 22, 17, 24, 25, 26, 27, 28 |
chr14:24709839 | c.847C>T | p.Pro283Ser | rs199422311 | DC, HHS | 12, 15 |
chr14:24709839 | c.847C>G | p.Pro283Ala | rs199422311 | DC | 12, 15 |
chr14:24709838 | c.848C>A | p.Pro283His | rs199422313 | DC | 12, 15 |
chr14:24709837 | c.849delC | p.Thr284GlnfsTer33 | / | ND, BMF | 18 |
chr14:24709837 | c.849_850insC | p.Thr284HisfsTer8 | rs199422315 | DC, AA | 12, 15 |
chr14:24709836 | c.850A>G | p.Thr284Ala | rs199422314 | DC | 12, 15 |
chr14:24709835 | c.851C>A | p.Thr284Lys | / | DC | 18 |
chr14:24709835 | c.851C>G | p.Thr284Arg | / | BMF, hair loss, dental loss, PD, short stature, osteoporosis | 18 |
chr14:24709829 | c.857delTinsGC | p.Met286SerfsTer5 | / | ND, BMF, microcephaly, low immunoglobulins | 18 |
chr14:24709826 | c.860T>C | p.Leu287Pro | rs199422316 | DC | 12, 15 |
chr14-24709824 | c.862T>C | p.Phe288Leu | rs199422317 | DC | 12, 15 |
chr14:24709821 | c.865C>T | p.Pro289Ser | rs1555304055 | N/A | 29 |
chr14:24709820 | c.865_866delinsAG | p.Pro289Ser | rs199422318 | DC | 12, 15 |
chr14:24709819 | c.867_868insC | p.Phe290LeufsTer2 | / | DC | 12 |
chr14:24709815 | c.871A>G | p.Arg291Gly | rs199422319 | DC | 12, 15 |
chr14:24709812 | c.872_875del | p.Arg291IlefsTer25 | / | DC, PD | 14 |
chr14:24709794 | c.892delC | p.Gln298ArgfsTer19 | rs199422320 | DC | 12, 15 |
chr14:24709508 | c.1090dup | p.Leu364ProfsTer9 | rs1566366182 | DC | / |
DC - Dyskeratosis congenita, HHS - Hoyeraal Hreidarsson syndrome, RS - Revesz syndrome, BMF - Bone marrow failure, AA - Aplastic anemia, PD - Pulmonary disease, ND - Nail dystrophy
The
DC is a rare genetic disorder with genetic and clinical heterogeneity. Patients with aplastic anemia should be screened for this rare condition, even when they do not have a classical clinical form. Reporting different cases increases our knowledge of the disease and its heterogeneity. Early diagnosis allows for prevention of severe invasive infections and non-infectious complications, thus improving the success of transplantation and overall prognosis of DC.