Dyskeratosis Congenita

Dyskeratosis Congenita – Introduction

rare genetic disorder characterized by defective telomere maintenance, leading to excessively shortened telomeres, diminished ability for cell proliferation, and organ dysfunction^(1,2,3)
about 70% of patients with clinical diagnosis of dyskeratosis congenita have a pathogenic variant(s) in 1 of the known dyskeratosis congenita-associated genes
variable clinical phenotype involving multiple organ systems^(1,2,3)
- classic dyskeratosis congenita characterized by triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia
- other major clinical manifestations include bone marrow failure and pulmonary fibrosis
associated with increased risk of hematological malignancy and solid tumors

Also Called

DC
DKC
Zinsser-Cole-Engman Syndrome

Definitions

short telomere syndromes (STS), or telomere biology disorders – a group of inherited conditions, including dyskeratosis congenita, that affect multiple organ systems and are caused by excessively short telomeres
somatic mosaic reversion – spontaneous correction of mutant allele (reversion to wild type) by mitotic recombination in subset of cells in patient bearing a germline mutation
genetic anticipation – refers to a younger age of onset and increased severity of the symptoms of a disease over successive generations within a family
silent carrier – a person with a disease-associated mutation who does not develop the expected clinical phenotype as a result of incomplete clinical penetrance

Types

classic dyskeratosis congenita^(1,2,3)
- characterized by ≥ 1 feature of mucocutaneous triad (lacy, reticular skin pigmentation; nail dystrophy; oral leukoplakia)
- associated with mutations in 1 of 13 known dyskeratosis congenita-associated genes
clinical variants – telomere diseases linked to classic dyskeratosis congenita by overlapping clinical features, very short telomeres, and mutations in genes important for telomere length maintenance^(1,2,3)
- telomere diseases associated with early presentation and neurodevelopmental defects (also called “severe variants”)
- Hoyeraal-Hreidarsson syndrome
  - characterized by cerebellar hypoplasia in addition to meeting diagnostic criteria for classic dyskeratosis congenita
  - additional features with high penetrance include
    - intrauterine growth retardation
    - microcephaly
    - developmental delay and intellectual disability
    - immunodeficiency that may progress to severe combined immunodeficiency syndrome (SCID)
    - bone marrow failure
  - typically presents in early childhood as a progressive, multisystem disorder
  - associated with
    - germline mutations in DKC1, TINF2, TERT, ACD, RTEL1, and PARN
    - de novo heterozygous mutations in TINF2
  - reported carrier frequency of the Hoyeraal-Hreidarsson syndrome-associated RTEL1 mutation is 1% in the orthodox Ashkenazi Jewish and 0.45% in the general Ashkenazi Jewish populations
  - telomeres are shorter than those in classic dyskeratosis congenita
  - high mortality rate in first decade of life due to immunodeficiency or bone marrow failure
  - Reference – Br J Haematol 2015 Aug;170(4):457 full-text, Pediatr Neurol 2016 Mar;56:62 full-text
- Revesz syndrome
  - characterized by bilateral exudative retinopathy in addition to meeting diagnostic criteria for classic dyskeratosis congenita
  - additional features may include
    - intrauterine growth retardation
    - intracranial calcification
    - cerebellar hypoplasia
    - sparse hair
    - bone marrow failure
  - typically presents before age 5 years
  - some patients have de novo mutations in TINF2 gene
  - telomeres are shorted than those in classic dyskeratosis congenita
- Coats plus
  - characterized by
    - findings similar to those in Revesz syndrome including
      - bilateral exudative retinopathy
      - intracranial calcification (characteristic involvement includes thalamus, basal ganglia, dentate, and deep cortex, with associated leukoencephalopathy and brain cysts)
      - intrauterine and postnatal growth retardation
      - sparse hair, nail dystrophy, and cutaneous changes
      - bone marrow involvement (though not typically bone marrow failure)
    - findings distinct from Revesz syndrome including
      - osteopenia with tendency to fracture and with poor bone healing
      - recurrent gastrointestinal hemorrhage due to vascular telangiectasias in the stomach, small intestine, and liver
  - most patients have biallelic mutations in CTC1
telomere diseases associated with single organ involvement
- idiopathic pulmonary fibrosis (IPF)
  - most common manifestation of disease due to shortened telomeres
  - about 8%-15% of familial cases and 1%-3% of sporadic IPF cases are associated with germline mutations in TERC or TERT; mutation in ACD, PARN, and RTEL1 also reported
- idiopathic aplastic anemia
  - associated with germline mutations in TERC and TERT
  - may present as
    - familial aplastic anemia
    - isolated aplastic anemia
  - some patients with apparently acquired aplastic anemia may have undiagnosed dyskeratosis congenita
- idiopathic cirrhosis of the liver – 7% of cases reported to be associated with germline mutations in TERT and TERC

Epidemiology

Incidence/Prevalence

rare, though specific prevalence of dyskeratosis congenita is unknown; at least 400 families worldwide are reported to be affected⁽³⁾

Associated Conditions

increased prevalence of neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD), intellectual disabilities, learning disabilities, or autism spectrum disorder⁽¹⁾

Etiology and Pathogenesis

Causes

mutation(s) in genes responsible for functioning and maintenance of telomeres^(1,2,3)
- to date 13 genes have been implicated
- may be inherited in X-linked, autosomal dominant, or autosomal recessive pattern
- de novo germline mutations also reported to occur, but with unknown frequency
60%-70% of patients have an identifiable germline mutation; it is likely that there are additional inherited causes that have not yet been identified^(1,2,3)
patients who do not have a mutation in 1 of the known genes reported to have most clinically severe phenotypes, with multiple features of dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome, or Revesz syndrome^(1,2,3)

Table 1: Genetic Mutations Known to Cause Dyskeratosis Congenita

Gene	Gene Product	Mode of Inheritance	Condition	Reported Frequency of Cases
DKC1	Dyskerin	X-linked	DC, HHS	17%-36%
TINF2	TIN2	Autosomal dominant or de novo	DC, HHS, RS	11%-24%
TERC	TERC	Autosomal dominant	DC, IPF, Cirrhosis, AA, MDS/AML	5%-10%
RTEL1	RTEL1	Autosomal dominant or recessive	DC, HHS	2%-8%
TERT	TERT	Autosomal dominant or recessive	DC, HHS,IPF, Cirrhosis, AA, MDS/AML	1%-7%
CTC1	CTC1	Autosomal recessive	DC, Coats Plus	1%-3%
WRAP53	TCAB1	Autosomal recessive	AR	3%
ACD	TPP1	Autosomal dominant or recessive	DC	< 1%
NOLA2	NHP2	Autosomal recessive	DC	< 1%
NOLA3	NOP10	Autosomal recessive	DC	< 1%
PARN	PARN	Autosomal recessive	DC, IPF	< 1%
STN1	STN1	Unknown	Coats plus	Unknown
NAF1	NAF1	Unknown	IPF	Unknown

Citation: Abbreviations: AA, aplastic anemia; AD, autosomal dominant; AML, acute myeloid leukemia; AR, autosomal recessive; DC, dyskeratosis congenita; HHS, Hoyeraal-Hreidarsson syndrome; IPF, idiopathic pulmonary fibrosis; MDS, myelodysplastic syndrome; RS, Revesz syndrome; XLR, X-linked recessive.

Pathogenesis

Normal Telomere Function

telomeres are TTAGGG hexameric tandem repeats found at the end of chromosomes that protect the chromosome from damage or from fusion with neighboring chromosomes^(1,2)
- normal DNA replication processes do not fully replicate the ends of chromosomes resulting in slight shortening of telomeres with each cell division
- telomeres have a minimum length after which
  - the cell cannot divide again
  - chromosome ends are recognized as DNA double-strand breaks
  - DNA damage response pathways and p53 activation lead to cell senescence or apoptosis
- telomere shortening
  - contributes to normal aging
  - functions to eliminate cells with a long proliferative history and at risk for replication dependent adverse genetic events
  - can be accelerated by environmental and lifestyle factors, such as exposure to toxic chemicals or chemotherapeutic agents, viral infections, physical inactivity, smoking, severe prolonged stress, and obesity
- telomeres are
  - protected by binding of proteins that form a chromosome cap structure
    - the cap protects the telomere from inappropriate repair reactions
    - core telomeric proteins (collectively referred to as the shelterin complex) include TRF1, TRF2, Rap1, TIN2, TPP1, and POT1
    - loss or dysfunction of the shelterin complex leads to “uncapping” of telomere, activation of a DNA damage response and ultimately senescence or apoptosis
  - replenished by telomerase
    - multi-subunit ribonucleoprotein enzyme which adds repetitive TTAGGG sequences to the end of the telomere
    - in somatic cells there is a limited amount of telomerase activity that slow down, but do not completely prevent, telomere attrition
    - adequate functioning of telomerase requires 7 molecules, including
      - DKC1, TERC, and TERT – genes that encode the telomerase enzyme
      - NOP10 and NHP2 – proteins that are involved in synthesis and assembly of telomerase
      - TCAB1 (encoded by WRAP53 gene) – provides transportation of telomerase to ends of telomere
      - TPP1 – protein that enables telomerase enzyme to dock with telomere ends
    - deficiency in any of these 7 molecules may results in
      - decreased telomerase activity at the telomere
      - failure of telomere length maintenance in the germline
      - decreased ability to slow down telomere attrition in tissues that depend on telomerase to maintain proliferative capacity throughout a normal life span
- Reference – Blood 2014 Oct 30;124(18):2775 full-text

Table 2: Components of Telomere Functioning

Component	Function
Shelterin complex	Composed of 6 core telomeric proteins including TRF1, TRF2, Rap1, TIN2, TPP1, and POT1Offers protection by binding to chromosome ends and forming a cap structure
Telomerase enzyme complex (multisubunit ribonucleoprotein polymerase)	Required for addition of repetitive telomeric sequences to single-stranded overhangsAddition of repetitive telomeric sequences to single-stranded overhangs viaComposed ofTERC – RNA molecule containing a short sequence in template region complementary to hexameric DNA sequenceTERT – catalytic protein that reverse transcribes telomeric DNA using TERCDyskerin – binds to RNA molecules such as TERC
NOP10 and NHP2	Required for synthesis and assembly of enzyme complex
TCAB1	Protein required for transportation of telomerase to telomere end
RTEL1	Unwinds specialized DNA structures prior to replication of telomeric DNA
CTC1	Interacts with DNA polymerase-alpha-primase for telomeric DNA replication and maintenance of correct telomere length
PARN	Associated with short telomeres; most likely affects the stability of DKC1, RTEL1, TRF1, or TERC

Telomere Function in Dyskeratosis Congenita

dyskeratosis congenita results from gene defects that interfere with telomere function and maintenance, resulting in excessively short telomeres^(1,2,3)
- defects in telomerase function
  - genes that encode components of telomerase (DKC1, TERC, TERT)
  - genes that encode proteins involved in telomerase
    - biogenesis/assembly (NOLA2, NOLA3)
    - transportation to telomere (WRAP53)
    - docking with telomere end (TPP1)
- defects in telomere capping and replication (TINF2, CTC1, RTEL1)
- defects in poly(A)-specific ribonuclease (PARN)
excessively short telomeres^(1,2)
- are recognized by cell as a DNA break, resulting in inappropriate repair reactions that lead to end-to-end fusions of chromosomes, genetic instability, and cell death
- affect ability of various tissues and organs to maintain themselves through normal cell division processes, which can result in an insufficient number of cells in various organs
- preferentially affect rapidly dividing tissues such as the skin, bone marrow, and gastrointestinal tract
- manifest as
  - bone marrow failure
    - bone marrow often affected, given it is a highly proliferative organ
    - deficiency in peripheral blood red blood cells (anemia), white blood cells (neutropenia), and platelets (thrombocytopenia) results from progressively hypocellular bone marrow
  - immune deficiency
    - immune cells are highly proliferative when stimulated by microbial organisms; thus lymphocytes are particularly susceptible to the effects of telomere dysfunction
    - lymphopenia is the most common immunological abnormality observed in dyskeratosis congenita (occurring in 70% of patients); associated with
      - preferential involvement of B cells, owing to
        
        relatively increased cell division during B lymphocyte development, causing acceleration of telomere shortening
        
        shorter half-life of B cells, compared with T lymphocytes
      - results in decreased B- and natural killer (NK)-cell count
    - secondary marked hypogammaglobulinemia affecting potentially all subtypes (immunoglobulin [Ig] G, IgM, and IgA) occurs with high frequency
    - impaired antibody response to specific environmental and vaccine-associated antigens impaired rendering vaccination ineffective
  - pulmonary fibrosis – etiology is not entirely clear
  - severe, chronic, noninfectious enteropathy with intractable diarrhea
    - a prominent feature of dyskeratosis congenita presenting in infancy
    - characterized by presence of mucosal inflammation and apoptosis similar to that observed in graft-versus-host disease
    - may result from impaired renewal of gut epithelium or altered mucosal immune function
  - liver cirrhosis
    - chronic liver injury stimulates hepatocellular proliferation, cell turnover and telomere loss, which in turn promotes cell proliferation arrest and apoptosis
    - telomere shortening by itself is associated with cirrhosis formation
  - osteopenia and osteoporosis
    - occurs when the rate of new bone production by osteoblasts is slower than the rate of resorption by osteoclasts
    - occurs with normal aging, but is accelerated in some patients with dyskeratosis congenita
    - premature thinning of bones may be due to
      - reduced ability of the shortened-telomere osteoblasts to differentiate and form normal bone
      - defects in mesenchymal stem cells which normally differentiate into osteoblasts
  - predisposition to malignancies as short telomeres result in increased propensity for chromosomal abnormalities
severity of condition is related to length of telomeres
- very severe telomere length deficit can be associated with inability to support normal organ development in specific embryonic tissues (for example, cerebellum or other parts of brain)
- short telomere syndromes that initially present in childhood usually affect bone marrow, resulting in pancytopenia (combination of anemia, neutropenia, and thrombocytopenia)
- less severe telomere shortening may not present with clinical manifestations until later in life
potential inability to restore telomere length in germline cells and early embryo, leading to offspring
- having telomeres that are shorter than normal at baseline (short telomere diseases are associated with genetic anticipation, a tendency to get worse from generation to generation)
- having intrauterine growth retardation

Revertant Somatic Mosaicism

revertant somatic mosaicism in the bone marrow has been reported with autosomal dominant dyskeratosis congenita, similar to that seen in Fanconi anemia⁽¹⁾
- presence in the same person of cells bearing mutation originating from germline, as well as subpopulation of cells in which mutant allele has reverted to wildtype
- hypothesized to occur via mitotic homologous recombination
- hematopoietic stem cells no longer bearing a dyskeratosis congenita-associated mutation may contribute to stabilizing or possibly lengthening telomeres, which can drive effective hematopoiesis
- no impact on shortened telomeres in somatic tissues such as skin, liver, or lung
- patients may have clinical features suggestive of dyskeratosis congenita with minimal hematopoietic abnormalities

History and Physical

Clinical Presentation

Phenotypic Spectrum

patients with dyskeratosis congenita can present with highly variable signs and symptoms, from classic findings in children to isolated hematological or other abnormalities in adults^(1,2,3)
clinical features of dyskeratosis congenita can develop at varying rates and ages; for example they may⁽³⁾
- be present at birth or during infancy
- present over the continuum of the first 2 decades of life
- first appear in adulthood
major clinical features of dyskeratosis congenita include ^(1,2,3)
- mucocutaneous triad (sufficient but not necessary)
  - lacy, reticular skin pigmentation
  - nail dystrophy
  - oral leukoplakia
- bone marrow failure (BMF)
- ophthalmologic findings, especially epiphora
- pulmonary fibrosis
additional features of variable severity may be present or may develop/worsen with age, including^(1,2,3)
- avascular necrosis of hips and shoulders
- urethral stenosis/phimosis
- esophageal strictures or webs
- hepatic fibrosis
- arteriovenous malformations (AVMs) in the lungs, liver, and gastrointestinal (GI) tract
- malignancies (may be the presenting feature)
progression of manifestations is unpredictable⁽³⁾

Table 3: Frequency of Clinical Findings in Dyskeratosis Congenita

Clinical Feature	Frequency in Patients with Dyskeratosis Congenita
Dysplastic nails	70%-88%
Reticulated skin pigmentation	67%-89%
Oral leukoplakia	47%-78%
Hematologic (cytopenias)	50%-86%
Epiphora	29%-31%
Dental abnormalities	13%-17%
Short stature	12%-20%
Learning difficulty and/or developmental delay	13%-25%
Pulmonary fibrosis	7%-20%
Premature grey hair and/or early balding	16%-19%
Esophageal narrowing, strictures, or webs	8%-17%
Intrauterine growth retardation or low birth weight	8%-9%
Microcephaly	6%-9%
Enteropathy	7%
Cerebellar hypoplasia and/or ataxia	5%-7%
Urethral stenosis, strictures, or phimosis	5%-7%
Osteopenia, osteoporosis, aseptic necrosis, or scoliosis	5%-6%
Undescended testes	3%-6%
Intracranial calcifications, leukomalacia or cerebral cysts	3%
Reduced hearing	1%-2%
Cardiac anomalies	1%

Citation: Reference – Intern Med J 2016 Apr;46(4):393.

Dermatologic and Mucocutaneous Manifestations

mucocutaneous triad consists of lacy reticulated (net-like) skin pigmentation, nail dystrophy, and oral leukoplakia^(1,2,3)
- usually presents in mid-to-late childhood; reported median age at presentation 8 years, but with high variability
- not all features need to be present for diagnosis and features do not need to present simultaneously
  - 80%-90% of patients reported to have ≥ 1 feature of triad
  - about 50% reported to have ≥ 2 features at diagnosis
- reticulated skin pigmentation
  - reticular or lacy hypo- or hyperpigmentation (but may also appear more punctate)
  - all areas of skin may be affected, though changes most commonly are gray-brown skin discoloration that occurs in areas of flexion (including the neck, shoulders, arms, and chest)
  - pigmentation may follow Blaschko lines and may become more pronounced with age
  - skin findings may appear similar to manifestations of graft-versus-host disease or other unrelated disorders associated with reticular skin pigmentation
- nail dystrophy
  - nail changes include ridging, thinning, peeling, flaking, slow growth, small nails (micronychia), and complete absence of the nail plate (anonychia)
  - fingernails and toenails can be affected, and changes may be subtle or severe and unequal
  - nail changes can be asynchronous, with affected nails adjacent to normal-appearing nails
- oral leukoplakia
  - may develop at any age; however tends to occur in patients younger than 50 years of age and in the absence of risk factors; like smoking or alcohol use
  - thickened, white patches on buccal mucosa, palate and/or gingiva, or along edges and surface of tongue that cannot be scraped off
  - when symptomatic, may present as oral mucosal sensitivity to spicy and acidic foods and mint-flavored toothpaste
  - may be associated with ulcerations that do not resolve within 2 weeks or recur over time
  - thought to be premalignant lesions associated with increased risk of developing head and neck squamous cell carcinoma (HNSCC)
  - can be easily identified during routine dental and medical examinations
  - best evaluated by an experienced otolaryngologist or oral surgeon
additional features of variable severity may be present or may develop/worsen with age^(1,2,3)
- atrophy of papillae on dorsum of tongue
- atrophy of skin markings on dorsal surfaces of hands and feet
- complete or patchy alopecia
- premature graying of hair, especially a gray forelock
- sparse eyebrows
- abnormal eyelash growth, such as sparse eyelashes and trichiasis (misdirected eyelashes)
- hyperhidrosis (excessive sweating)
- hyperkeratosis (thickening of skin) of palms and soles
- adermatoglyphia (lack of fingerprints) that develops over time
- telangiectasias
- hyperpigmentation of gums, tongue, palms, and soles
- precancerous skin lesions
dermatologic review of patients with mucocutaneous findings can be useful for diagnosis and as baseline for future surveillance of skin cancers⁽²⁾

Bone Marrow Failure

BMF^(1,2)
- generally defined as bone marrow cellularity less than normal for age plus ≥ 1 peripheral blood cytopenia (absolute neutrophil count, hemoglobin, or platelet count below lower limit of normal for age)
- cytopenias reported in 50%-86% of cases
- > 80% of patients with classic dyskeratosis congenita will manifest BMF by age 30
- low platelet count usually the first cytopenia to appear, followed by anemia or neutropenia
- age of onset is variable
  - often starts in second decade of life
  - may present with progressive BMF early in life before appearance of other clinical features of dyskeratosis congenita
  - may appear later in life (or not at all) in patients with mutations in TERC or TERT
- can develop before (and in some cases never be associated with) mucocutaneous features
- extent of bone marrow failure can be mild to severe
- the most significant cause of mortality in patients with dyskeratosis congenita (60%-70% of deaths)
clinical features of bone marrow failure may include
- anemia (often macrocytic), presenting as fatigue, pallor, weakness, dyspnea, and/or exercise intolerance
- thrombocytopenia, presenting as skin or mucosal hemorrhage including
  - easy bruising
  - petechiae
  - epistaxis
  - menorrhagia in postmenarchal females
- neutropenia, which can predispose patients to infections
- Reference – Br J Haematol 2016 Jan;172(2):187, Pediatr Clin North Am 2013 Dec;60(6):1311 full-text
see Management for more information on management of bone marrow failure in patients with dyskeratosis congenita

Pulmonary Fibrosis

pulmonary fibrosis^(1,2,3)
- reported in 7%-20% of cases
- patterns of presentation of telomere-related pulmonary fibrosis⁽¹⁾
  - presentation early in life
    - typically after onset of bone marrow failure
    - may be accelerated by exposure to hematopoietic stem cell transplantation conditioning regimens
      - onset within 1 year following myeloablative preparatory regimens
      - onset after 1 year with nonmyeloablative regimens
  - presentation in adulthood
    - may be first life-threatening complication; in these cases usually in patients > 30 years old
    - after fourth decade, pulmonary fibrosis may be dominant feature and occur in absence of mucocutaneous features and bone marrow failure
- presenting features include
  - chronic cough and exertional dyspnea
  - inspiratory rales and digital clubbing on physical exam
  - restrictive pattern on pulmonary function tests
  - decreased diffusion capacity for carbon monoxide (DL_CO)
  - diffuse interstitial markings in high-resolution noncontrast computed tomography (CT) imaging of the chest
- second leading cause of mortality in patients with dyskeratosis congenita (10%-15% of deaths)

Growth and Development Delays

most individuals with dyskeratosis congenita have normal intelligence and achieve normal developmental motor milestones⁽¹⁾
growth delay, developmental delay, and/or learning disability may be present, especially in patients with Hoyeraal-Hreidarsson and Revesz Syndrome^(1,3)

HEENT Manifestations

ophthalmologic manifestations^(1,2,3)
- reported in approximately 40% of patients with dyskeratosis congenita
- most common finding in patients with dyskeratosis congenita is obliteration of the lacrimal drainage system often due to absent punctae or nasolacrimal duct obstruction; may present with
  - epiphora (constant tearing)
  - frequent episodes of conjunctivitis
  - episodes of blepharitis (inflammation of the eyelids)
  - corneal ulcers
- anterior segment and adnexa (lids, lashes and lacrimal system)
  - punctal atresia
  - nasolacrimal duct obstruction
  - trichiasis (misdirected eyelashes)
  - loss of eyelashes
  - entropion (in-turning of the eyelids and eyelashes)
  - ectropion (out-turning of the eyelids and eyelashes)
  - conjunctivitis
  - corneal scarring
  - corneal ulceration and perforation
  - cataracts
  - blepharitis
- posterior segment
  - optic nerve atrophy
  - retinal vascular changes have been described in patients with dyskeratosis congenita; can include
    - perivascular sheathing (atherosclerosis of the vessels)
    - retinal hemorrhage
    - areas of nonperfusion
    - retinal neovascularization (especially patients with Hoyeraal-Hreidarsson syndrome)
    - bilateral exudative retinopathy, which can lead to blindness (required for diagnosis of Revesz syndrome)
hearing loss (deafness is rare)^(1,3)
dental involvement^(1,2,3)
- about 74% of patients with dyskeratosis congenita have dental abnormalities
- dental abnormalities include
  - delayed eruption of teeth or hypodontia
  - extensive dental caries or tooth loss
  - crowding
  - periodontal disease
  - taurodontism (enlarged tooth pulp chambers)
  - short dental roots resulting in unfavorable root/crown ratios

Gastrointestinal and Hepatic Manifestations

GI manifestations^(1,2,3)
- reported in about 16% of individuals with dyskeratosis congenita
- GI manifestations include
  - esophageal stenosis and/or webbing
    - typically occurs in patients with classic mucocutaneous features
    - may present
      - soon after birth as poor feeding, regurgitation, and failure to thrive
      - in older children and adults, often associated with selective chewing and food avoidance
  - enteropathy
    - primarily affects the small bowel
    - often present with subtle and chronic complaints including
      - nausea
      - early satiety
      - nonspecific abdominal pain
      - food intolerance
      - difficulty with weight gain
      - diarrhea
      - food allergies
      - failure to thrive (in extreme cases)
  - enterocolitis
    - the most serious and life-threatening GI complication of dyskeratosis congenita
    - primarily affects the colon
    - particularly prevalent in Hoyeraal-Hreidarsson syndrome (may be 1 of its initial presentations)
    - symptoms include
      - abdominal pain
      - failure to thrive
      - bloody diarrhea
  - gastrointestinal tract bleeding due to ulceration, telangiectasias, or varices (may also be present in Revesz syndrome)
hepatic manifestations^(1,2,3)
- hepatic manifestations include
  - hepatopulmonary syndrome
  - hepatic cirrhosis
  - idiopathic noncirrhotic portal hypertension
  - hepatocellular carcinoma
- patients may present with
  - fatigue
  - jaundice
  - hematemesis
  - abdominal distension
  - peripheral edema
  - signs of hepatic insufficiency (including jaundice, spider telangiectasias, palmar erythema, gynecomastia)
  - signs of portal hypertension (splenomegaly, ascites)
  - laboratory tests showing
    - elevated hepatocellular enzymes (commonly with aspartate aminotransferase [AST] greater than alanine aminotransferase [ALT])
    - elevated canalicular enzymes (alkaline phosphatase [ALP] and gamma-glutamyltransferase [GGT])
    - low serum albumin
    - prolonged prothrombin time
    - elevated ammonia
  - imaging may reveal ascites, splenomegaly, esophageal varices and a nodular hepatic surface with increased echogenicity
- patients taking androgens are particularly susceptible to developing liver toxicity as evidenced by increase in transaminase or bilirubin level

Genitourinary Tract Involvement

genitourinary tract involvement^(1,2,3)
- microscopic hematuria due to hemorrhagic cystitis
- pubertal delay
- in men
  - urethral strictures
    - typically present with obstructive voiding symptoms including
      - straining with urination
      - incomplete bladder emptying
      - weak urine stream
    - may be associated with
      - hematuria
      - frequent urinary tract infections
      - prostatitis
      - epididymitis
      - bladder stones
  - phimosis resulting in difficulty in urination, balanitis, or urinary tract infections
  - lichen planus lesions
  - hypogonadism
- in women
  - labial adhesions and leukoplakia
  - hymenal and urethral strictures
  - excessive menstrual bleeding
  - premature ovarian insufficiency

Endocrine and Musculoskeletal Manifestations

endocrine manifestations⁽¹⁾
- short stature – prevalence varies between cohorts from extremely rare to 20%
- hypogonadism reported in 6% of patients
- rarely, growth hormone deficiency and hypothyroidism
musculoskeletal disease^(1,3)
- avascular necrosis of hip and shoulders
  - reported in about 10% of patients (mostly adults)
  - may result in pain, degenerative arthritis, and decreased function of the joint
- osteoporosis
- spontaneous bone fractures may occur in patients with severe manifestations of dyskeratosis congenita in childhood, particularly those with Coats plus, Hoyeraal-Hreidarsson, or Revesz syndrome

Neurologic Manifestations

neurologic manifestations^(1,2,3)
- microcephaly (more common in Hoyeraal-Hreidarsson syndrome)
- cerebellar hypoplasia (required for diagnosis of Hoyeraal-Hreidarsson syndrome)
- intracranial calcification (characteristic feature of Coats plus and may also be present in Revesz syndrome)
- ataxia
neuropsychiatric effects including mood disorders, anxiety, psychosis, or adjustment disorder
neurocognitive manifestations including pervasive developmental disorder, learning disorders, attention deficit hyperactivity disorder, intellectual disabilities

Immunologic Manifestations

patients can present with a spectrum of immunological features ^(1,3)
- lymphopenia in about 70% of patients with dyskeratosis congenita
- decreased B- and natural killer (NK)-cell count commonly found
- common variable immunodeficiency (CVID)
- severe combined immunodeficiency (SCID)

Vascular Manifestations

retinal telangiectasias
GI telangiectasias
- described in the stomach, intestine, and liver of patients with Coats plus
- may present as life threatening GI bleeding regardless of the underlying cause; thus a potentially severe complication of dyskeratosis congenita
pulmonary vascular malformations
- hepatopulmonary syndrome is described as
  - pulmonary vascular dilation due to liver disease of any form that leads to deficit in arterial oxygenation
  - can occur in patients with or without portal hypertension
  - patients with dyskeratosis congenita may be at risk of hepatopulmonary syndrome due to the increased frequency of underlying liver disease in this population
- pulmonary AVMs unrelated to hepatopulmonary syndrome
  - may be microscopic and multiple, or macroscopic pulmonary
  - may lead to right-to-left shunting of blood, which causes a deficit in arterial oxygenation and progressive respiratory insufficiency

Manifestations That may Indicate Subtypes of Dyskeratosis Congenita

Hoyeraal-Hreidarsson Syndrome^(1,2,3)
- cerebellar hypoplasia (required for diagnosis)
- intrauterine and postnatal growth restriction
- microcephaly
- developmental delay and intellectual disability
- immunodeficiency
- bone marrow failure
Revesz syndrome^(1,2,3)
- bilateral exudative retinopathy, also known as Coats disease (required for diagnosis)
- intrauterine growth restriction
- intracranial calcification
- fine, sparse hair
- bone marrow failure
Coats plus^(1,2)
- distinctive pattern of intracranial calcification involving thalamus, basal ganglia, dentate, and deep cortex, with associated leukoencephalopathy and brain cysts
- intrauterine and postnatal growth restriction
- retinal telangiectasia and exudative retinopathy (consistent with Coats disease)
- osteopenia with tendency to fracture and with poor bone healing
- recurrent gastrointestinal hemorrhage due to vascular ectasias in the stomach, small intestine, and liver

History

Chief Concern (CC)

presenting symptoms depend on clinical manifestations; see Clinical presentation

History of Present Illness (HPI)

clinical features of dyskeratosis congenita can develop at varying rates and ages; some may not be present at all^(1,3)
- features may be present at birth or during infancy, may develop in first 2 decades of life, or present in adulthood
- some variants of dyskeratosis congenita (Hoyeraal-Hreidarsson syndrome, Revesz syndrome, Coats plus) tend to present in first months to 2 years of life

Past Medical History (PMH)

ask about prior history of cancer, such as⁽¹⁾
- myelodysplastic syndrome
- acute myeloid leukemia
- head and neck cancer, especially squamous cell carcinoma of tongue
- anogenital squamous cell carcinoma
ask about history of ^(2,3)
- skin and/or nail abnormalities
- developmental delay
- eye or vision abnormalities, including persistent tearing or tear duct issues
- dental abnormalities
- low blood counts or liver abnormalities
- pulmonary fibrosis or respiratory difficulties
- urinary stricture/hematuria/phimosis
- receding hairline or premature graying

Family History (FH)

ask about family history of diseases suggesting telomere disorders, such as^(1,2)
- dyskeratosis congenita
- pulmonary fibrosis
- liver fibrosis or cirrhosis of nonalcoholic, noninfectious etiology
- bone marrow failure, myelodysplastic syndrome, or acute myeloid leukemia
- cancers, particularly in relatives < 50 years old, including
  - head and neck (especially squamous cell carcinoma of tongue)
  - anogenital squamous cell carcinoma
ask about any history of death in infancy or childhood due to immunodeficiency⁽¹⁾

Physical

physical exam findings depend on clinical manifestations; see clinical presentation

Diagnosis

Making the Diagnosis

suspect dyskeratosis congenita in patients who present with either of the following^(2,3)
- ≥ 2 features of mucocutaneous triad (abnormal skin pigmentation, nail dystrophy, and oral leukoplakia)
- ≥ 1 feature of triad plus 2 or more additional disease-associated clinical manifestations
confirm diagnosis in patients with clinical features or at-risk family members using molecular testing⁽¹⁾
- telomere length testing (telomere lengths below first percentile for age in more than 1 lymphocyte subset is consistent with diagnosis)
- gene sequencing to identify pathogenic variant(s)

Table 4: Clinical Diagnostic Criteria

Condition	Clinical Diagnostic Criteria	Additional Features
DC	Mucocutaneous triad OR1 component of the mucocutaneous triad, bone marrow failure and 2 other DC manifestations OR2 or more features associated with DC (such as pulmonary fibrosis, bone marrow failure) and very short (< first percentile for age) telomeres	Very short telomeres (< first percentile for age), and pathogenic DC mutations
Hoyeraal-Hreidarsson syndrome	Growth retardationDevelopmental delayMicrocephalyBone marrow failureImmunodeficiencyCerebellar hypoplasia	Very short telomeres (< first percentile for age), and pathogenic DC mutations
Revesz syndrome	Bilateral exudative retinopathyCentral nervous system calcificationsIntrauterine growth retardationBone marrow failureFine sparse hair	Very short telomeres (< first percentile for age), and pathogenic DC mutations
Coats plus syndrome	Intracranial calcificationRetinal telangiectasia and exudateIntrauterine growth retardationOsteopenia	Mutation in gene known to be involved in short telomere disorders +/− TL < first percentile for age
Isolated subtype	Isolated presentation of condition	NA

Citation: Abbreviations: DC, dyskeratosis congenita; NA, not applicable.

prenatal testing and preimplantation genetic diagnosis are possible if the pathogenic variant has been identified for appropriate patients^(1,3)
refer individuals with suspected diagnosis to specialist with expertise in dyskeratosis congenita⁽¹⁾

Differential Diagnosis

skin disorders that can be associated with reticular skin pigmentation^(1,2)
- dermatopathia pigmentosa reticularis – rare autosomal dominant disorder caused by mutations in keratin 14, characterized by triad of generalized reticulate hyperpigmentation, nonscarring alopecia, and onychodystrophy (Indian J Dermatol 2016 Jul-Aug;61(4):468 full-text)
- Naegeli (Naegeli-Franceschetti-Jadassohn) syndrome – rare autosomal dominant disorder caused by mutations in keratin 14, characterized by brown-grey reticulate hyperpigmentation, mild palmoplantar hyperkeratosis, absence of a recognizable dermatoglyphic pattern on the finger tips, nail dysplasia, and enamel defects (Eur J Med Genet 2011 May-Jun;54(3):231)
- Kindler syndrome – rare subtype of inherited epidermolysis bullosa, characterized by skin fragility and formation of acral blisters starting at birth, diffuse cutaneous atrophy, photosensitivity, poikiloderma, diffuse palmoplantar hyperkeratosis, and pseudosyndactyly (Gene Reviews 2016 Dec 1)
- poikiloderma with neutropenia (also known as poikiloderma Clericuzio type)
  - usually starts on limbs and as papules before becoming more extensive poikiloderma
  - oral leukoplakia is rare or absent
- graft-versus-host disease
disorders with nail dysplasia such as^(1,2,3)
- nail patella syndrome
  - rare autosomal dominant disorder characterized by dysplastic nails, absent or hypoplastic patella, elbow dysplasia, and iliac horns (Pediatr Nephrol 2017 Oct;32(10):1845)
  - lacks extensive poikilodermic changes
  - oral leukoplakia is rare or absent
- twenty-nail dystrophy (or trachyonychia) – condition involving all 20 nails characterized by longitudinal ridging, pitting, and roughening of nail surface (Skin Appendage Disord 2016 Sep;2(1-2):7 full-text)
- keratoderma with nail dystrophy and motor-sensory neuropathy
  - primarily affects palmoplantar surfaces and do not have hematological manifestations
  - oral leukoplakia is rare or absent
- poikiloderma with neutropenia (also known as poikiloderma Clericuzio type)
  - usually starts on limbs and as papules before becoming more extensive poikiloderma
  - oral leukoplakia is rare or absent
- pachyonychia congenita
  - primarily affects palmoplantar surfaces and does not have hematological manifestations
  - oral leukoplakia is rare or absent
- lichen planus
disorders with oral lesions, such as oral lichen planus, are similar in appearance to oral leukoplakia⁽¹⁾
disorders with pancytopenia or bone marrow failure
inherited bone marrow disorders such as^(1,2,3)
- Fanconi anemia – if present, skin pigmentation abnormalities are usually more generalized, and include hyperpigmentation and distinct cafe au lait lesions
- Shwachman-Diamond syndrome – dominant mucocutaneous features are absent
- Diamond-Blackfan anemia – dominant mucocutaneous features are absent
for differential diagnosis of acquired pancytopenia or bone marrow failure, see Aplastic anemia
disorders causing pulmonary fibrosis, including idiopathic pulmonary fibrosis

Testing Overview

prior to genetic testing, offer genetic counseling about risk, benefits, and limitations of testing⁽¹⁾
perform molecular testing to confirm clinical diagnosis of dyskeratosis congenita⁽¹⁾
- telomere length testing (telomere lengths in lymphocytes below first percentile for age are consistent with diagnosis)
- gene sequencing to identify pathogenic variant(s)
additional testing following initial diagnosis to determine extent and/or complications of disease; tests to consider may include^(1,2,3)
- evaluation for bone marrow failure/baseline hematologic status
  - blood tests including complete blood count and absolute reticulocyte count
  - bone marrow aspiration and biopsy, including cytogenetic evaluation
  - human leukocyte antigen (HLA) typing of patient, unaffected siblings, and parents in case of possible need for hematopoietic stem cell transplant (HSCT)
- evaluation of pulmonary function (refer to pulmonologist if patient is symptomatic)
  - baseline pulmonary function (refer to pulmonologist if abnormal results) with diffusing capacity of lung for carbon monoxide (DL_CO)
  - imaging to evaluate for pulmonary fibrosis or pulmonary arteriovenous malformations
  - lung biopsy if indicated, using least invasive procedure that is feasible
- evaluation of gastrointestinal (GI) tract
  - barium swallow or esophagram followed by confirmatory endoscopic evaluation in patients with suspicion of web or stricture
  - upper endoscopy with biopsies of the proximal small bowel, and colonoscopy in patients with suspicion of telomere-associated enteropathy
  - upper and lower tract endoscopy to diagnose source of bleeding in patients with suspicion of GI bleeding
- evaluation for hepatic manifestations and baseline hepatic function
  - blood tests, including liver function tests
  - imaging or liver biopsy if clinically indicated
- evaluation for immunodeficiency
- other tests depending on clinical presentation may include
  - brain magnetic resonance imaging (MRI) to evaluate for cerebellar hypoplasia or intracranial calcifications if early-onset neurologic findings or many other complications are present
  - eye exam by an ophthalmologist to evaluate for anterior and posterior ophthalmologic manifestations
  - bubble echocardiography to evaluate for right-to-left shunting and pulmonary arteriovenous malformations
  - neuropsychological testing
  - audiogram or auditory brain-stem evoked response testing to test for hearing loss
  - testosterone, luteinizing hormone, and follicle stimulating hormone levels in patients with suspicion of hypogonadism or growth hormone deficiency
  - imaging for evaluation for avascular necrosis (AVN) of the humeral or femoral head
  - dual energy absorptiometry (DXA) scan to evaluate bone mineral density (BMD) and evaluation for osteoporosis
  - imaging studies, such as retrograde urethrography, voiding cystourethrography, or cystoscopy to evaluation for suspected urethral strictures

Blood Tests

Evaluation of Bone Marrow Failure

blood tests used to evaluate for bone marrow failure (in combination with bone marrow biopsy) to determine baseline hematologic status^(1,2,3)
- complete blood count, including mean corpuscular volume (MCV)
  - cytopenias reported in 50%-86% of cases
  - low platelet count is usually the first cytopenia to appear followed by anemia or neutropenia
  - elevated MCV
    - may be only hematological abnormality
    - increases index of suspicion for inherited rather than acquired aplastic anemia
  - if MCV elevated, consider measuring red blood cell folate and vitamin B12
- absolute reticulocyte count
other tests to consider include
- fetal hemoglobin F and erythropoietin levels (elevated levels can suggest inherited bone marrow failure syndromes)
- chromosome breakage test to rule out Fanconi anemia
diagnosis of bone marrow failure based on⁽¹⁾
- blood counts that are persistently below normal for age in conjunction with presence of hypocellular bone marrow with blast count < 5%
- exclusion of other causes of low blood counts, such as infection, medications, peripheral blood cell destruction, and nutritional deficiencies
classification of bone marrow failure in dyskeratosis congenita based on degree of peripheral blood cytopenia in most severely affected cell lineage (adapted from consensus guidelines for Fanconi anemia)⁽¹⁾
- thrombocytopenia usually occurs first and is followed by anemia or neutropenia

Table 5: Severity of Bone Marrow Failure

Classification	Platelet Count	ANC	Hemoglobin
Mild	50 to < 150 × 10⁹/L	1 to < 1.5 × 10⁹/L	Less than normal for age to ≤ 8 g/dL
Moderate	20 to < 50 × 10⁹/L	0.5 to < 1 × 10⁹/L	Less than normal for age to ≤ 8 g/dL
Severe	< 20 × 10⁹/L	< 0.5 × 10⁹/L	< 8 g/dL

Citation: Abbreviation: ANC, absolute neutrophil count.

Evaluation of Other Manifestations

baseline blood tests to evaluate for hepatic manifestations, including ⁽¹⁾
- aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
- alkaline phosphatase (ALP)
- gamma-glutamyltransferase (GGT)
- bilirubin (conjugated and unconjugated)
- albumin
- prothrombin time
- ammonia
in patients with suspicion of hypogonadism or growth hormone deficiency, check testosterone, luteinizing hormone, and follicle stimulating hormone levels⁽¹⁾
evaluation for immunodeficiency⁽¹⁾
- quantitative immunoglobulin (Ig) levels for IgG, IgM, IgA, and IgE
- flow cytometry to quantify lymphocyte subsets (T-, B-, and NK-cell percentages and absolute numbers)
- lymphocyte proliferation panel for response to mitogens (phytohemagglutinin, concanavalin A and pokeweed) and specific antigens (tetanus toxoid and candida)
- tetanus, diphtheria, poliomyelitis, and pneumococcal antibody titers
- measurement of IgM isohemagglutinin titers

Imaging Studies

Lung Imaging

when pulmonary manifestations are suspected, consider additional testing (beyond pulmonary function testing)^(1,3)
- x-ray or noncontrast high-resolution computed tomography (CT) to assess for pulmonary fibrosis
  - noncontrast high-resolution CT usually demonstrates diffuse interstitial markings
  - most common radiographic pattern is usual interstitial pneumonia, though this pattern is not generally seen in children
in middle-aged and older asymptomatic adults, consider noncontrast high-resolution CT (in addition to other noninvasive testing) to establish a clinical baseline⁽¹⁾

Abdominal Imaging

if liver function tests are abnormal or physical exam suggests liver enlargement, perform imaging to assess liver involvement with⁽¹⁾
- abdominal ultrasound (preferred) — may show splenomegaly, ascites, and nodular hepatic surface with increased echogenicity
- FibroScan (transient ultrasound elastography ) to evaluate presence of fibrosis
- magnetic resonance imaging (MRI)
consider diagnostic studies such as endoscopy to evaluate for varices in patients with evidence of liver fibrosis or cirrhosis

Other Imaging

consider additional imaging when evaluating other manifestations^(1,3)
- baseline bone mineral density scan to assess for osteopenia
  - baseline study at around age 14 years
  - in patients with suspicion of hypogonadism or growth hormone deficiency
  - prior to and 1 year after hematopoietic stem cell transplantation (HSCT)
- x-ray, bone scan, or MRI for evaluation for avascular necrosis (AVN) of the humeral or femoral head
- brain MRI to evaluate for cerebellar hypoplasia or intracranial calcifications (suggestive of Hoyeraal-Hreidarsson syndrome orRevesz syndrome) if early-onset neurologic findings or other complications are present
- bubble echocardiography to assess for pulmonary arteriovenous malformations

Biopsy and Pathology

Bone Marrow Aspiration and Biopsy

bone marrow aspiration and biopsy used to evaluate for bone marrow failure (BMF) and determine baseline hematologic status, regardless of whether BMF is present or not^(1,2,3)
- aspirate determines whether cells within the bone marrow are morphologically normal or dysplastic
- biopsy assesses marrow architecture and cellularity
diagnosis of bone marrow failure based on presence of hypocellular bone marrow with blast count < 5% in conjunction with blood counts that are persistently below normal for age⁽¹⁾
perform studies on bone marrow to determine presence of abnormalities ^(1,3)
- cytogenetic analysis by G-banding
- fluorescence in situ hybridization (FISH) to detect 5q-, 7q-/monosomy 7, or trisomy 8 and 20q- (common clonal cytogenetic abnormalities associated with myelodysplastic syndrome [MDS])
- presence of a cytogenetic clone by itself (without morphologic evidence of MDS) does not necessarily indicate a diagnosis of MDS
- abnormal cytogenetic clones can remain stable or progress; once identified, may require more frequent monitoring of bone marrow and blood counts
findings that may be associated with alternative diagnosis⁽¹⁾
- > 20% blasts in marrow may indicate acute myeloid leukemia (AML)
- significant dyspoiesis may indicate MDS
- some degree of morphologic abnormality in erythroid, myeloid, or megakaryocytic lineages is common in patients with dyskeratosis congenita and other bone marrow failure syndromes, and does not always indicate diagnosis of MDS or progression to AML

Lung Biopsy

risks and benefits of lung biopsy (surgical or thorascopic) should be carefully reviewed, especially if biopsy not anticipated to change clinical management⁽¹⁾
bronchoscopy or thoracoscopic lung biopsy is suggested when etiology of lung disease is unclear^(1,2)
- bronchoscopy with collection of bronchoalveolar lavage fluid and transbronchial biopsies may provide useful diagnostic material
- bronchoscopy associated with lower risk of adverse events than open surgical lung biopsy
- typically characterized by
  - mix of cellular inflammatory infiltrates
  - epithelial cell loss
  - interstitial prominent fibrosis
  - abnormalities of pulmonary vasculature and impaired oxygen exchange
  - different histopathologic pattern than seen in idiopathic pulmonary fibrosis

Liver Biopsy

liver biopsy may rarely be indicated if liver function tests and other imaging is abnormal; however there is increased risk of bleeding from this procedure in patients with thrombocytopenia or coagulopathy⁽¹⁾
histology may reveal⁽¹⁾
- distortion of architecture with fibrosis connecting portal areas
- perisinusoidal fibrosis
- inflammatory infiltrates
- macrovesicular steatosis and Mallory bodies
- iron accumulation in hepatocytes

Pulmonary Function Tests

perform pulmonary function evaluation at baseline (refer to pulmonologist if abnormal results)^(1,2,3)
- pulse oximetry, pulmonary function tests, and carbon monoxide diffusion capacity (DL_CO testing)
- use 6-minute walk test in children unable to perform pulmonary function tests
pulmonary fibrosis associated with restrictive pattern on pulmonary function tests and decreased DL_CO⁽¹⁾
in middle-aged and older asymptomatic adults, consider noninvasive testing with spirometry, plethysmography, and DL_CO, as well as noncontrast high-resolution chest computed tomography (CT) to establish a clinical baseline⁽¹⁾

Molecular Testing

Telomere Length Testing

methods to measure telomere length^(1,2,3)
- multicolor flow cytometry combined with fluorescence in situ hybridization (flow-FISH) is only validated technique for diagnosis of dyskeratosis congenita
  - provides measurement of telomere length in cells within a variety of leukocytes
  - 6-cell panel assay may be more useful than 2-panel test
  - uses fresh peripheral blood cells and should be performed before hematopoietic stem cell transplantation (HSCT); after HSCT the donor, rather than patient cells, would be analyzed
- other methods provide estimates of telomere length
  - assays include
    - quantitative polymerase chain reaction (qPCR) – provides relative estimate of telomere length with measurements of telomeric repeat-containing DNA and an internal single copy control
    - Southern blot analysis – estimates median telomere length of total leukocytes within the sample using an electrophoretic pattern of DNA
  - reported to be less accurate, reproducible, sensitive, and specific than telomere measurements by automated multicolor flow-FISH
indications for testing⁽¹⁾
- perform as initial test in
  - all patients with suspected diagnosis of dyskeratosis congenita
  - all patients with aplastic anemia
    - bone marrow failure may precede clinical manifestations of dyskeratosis congenita
    - especially if being considered for HSCT
    - diagnosis of dyskeratosis congenita may influence management strategies, including medications, conditioning regimens, and donor selection for HSCT
  - patients where dyskeratosis congenita suspected in absence of clinical manifestations
if revertant somatic mosaicism is suspected, for example in patients with solely extra hematopoietic manifestations of dyskeratosis congenita, DNA from nonhematopoietic tissue (such as skin fibroblasts) should be analyzed⁽¹⁾
interpretation of results⁽¹⁾
- should be assessed by those experienced in interpreting these results and in conjunction with clinical circumstances and family history (very short telomeres alone are not sufficient to make diagnosis)
- diagnosis consistent with dyskeratosis congenita if telomere lengths below first percentile for age in > 1 lymphocyte subset (granulocytes, CD45+ naive T cells, CD45- memory T cells, CD20+ B cells, CD57+ natural killer [NK]/NKT cells)

Gene Sequencing

genetic testing used to identify pathogenic variant(s) that cause dyskeratosis congenita^(1,2,3)
- diagnosis is based on presence of damaging or deleterious mutation in dyskeratosis congenita-associated gene(s)
- about 70% of patients with clinical diagnosis of dyskeratosis congenita have a pathogenic variant(s) in 1 of the 13 known dyskeratosis congenita-associated genes
  - most common pathogenic variants are CTC1, DKC1, RTEL1, TERC, TERT, and TINF2
  - pathogenic variants reported in only a few families are ACD, NOLA2, NOLA3, PARN, and WRAP53
- point mutations are most common defect identified
- absence of a known mutation does not exclude diagnosis in a patient who may only have limited clinical manifestations
prior to genetic testing, offer genetic counseling about risk, benefits, and limitations of testing (which can vary by laboratory)⁽¹⁾
genetic testing approaches^(1,2,3)
- serial single-gene testing
  - appropriate if a mutation of a particular gene is most likely based on clinical and laboratory findings, family history, or inheritance pattern
  - perform sequence analysis of suspected gene first, then perform gene-targeted deletion/duplication analysis if no pathogenic variant(s) are found
    - sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic
    - gene-targeted deletion/duplication analysis detects intragenic deletions or duplications
  - in persons of Ashkenazi Jewish descent, perform targeted gene analysis to identify mutations in RTEL1 first
- multigene panel may also be considered; which genes are included in panel can vary by laboratory
- whole exome or whole genome sequencing, when available
  - as there are now multiple genes known to cause dyskeratosis congenita, whole exome or whole genome sequencing may be a more comprehensive modality
  - consider if serial single-gene testing (and/or use of multigene panel) does not confirm diagnosis
  - may suggest a diagnosis not previously considered
  - involves obtaining samples from the patient, parents, and siblings to interpret data and identify mutation
additional considerations⁽¹⁾
- female carriers of DKC1 mutations may present with clinical features of dyskeratosis congenita
  - determining carrier status of DKC1 mutation in females may be useful
  - if DKC1 testing not available, consider X chromosome inactivation analysis using human androgen receptor assay
- preimplantation or prenatal genetic diagnosis is possible if the pathogenic variant has been identified
  - prenatal testing performed using fetal cells obtained by chorionic villus sampling (typically performed around 10-12 weeks gestation) or amniocentesis (typically performed at 15-18 weeks gestation); DNA extracted from fetal cells used to test for mutation or human leukocyte antigen type
  - preimplantation genetic diagnosis performed using in vitro fertilization and analyzing cell(s) from each embryo for mutation and/or desired human leukocyte antigen type

Management

Management Overview

management should involve a multidisciplinary approach depending on symptoms, severity of disorder, and associated complications
to establish extent of disease and management needs, baseline assessment of clinical manifestations is suggested in patients with confirmed diagnosis of dyskeratosis congenita⁽³⁾
offer supportive measures, such as counseling and lifestyle management
for those wishing to have children, offer prenatal screening or preimplantation genetic selection of unaffected human leukocyte antigen (HLA)-matched embryo
patients will need surveillance by multidisciplinary providers for dyskeratosis congenita-associated complications⁽²⁾
focus of discussion in this topic is on treatment of hematologic and pulmonary complications of dyskeratosis congenita
management of bone marrow failure (BMF)⁽¹⁾
- upon diagnosis, consult hematologist with expertise in evaluation, monitoring, and management of dyskeratosis congenita and BMF
- discuss treatment options with young patients with any degree of cytopenias; consider monitoring blood counts in older patients with mild cytopenias
- refer family members to appropriate medical and genetic counseling; consider HLA typing and genetic testing of immediate family members to assess availability of potential hematopoietic stem cell donors; initiate preliminary unrelated donor search to understand whether this option would be realistic
- treatment options depend on severity of BMF, and include
  - surveillance for those with mild BMF
  - hematopoietic stem cell transplantation (HSCT) for those with significant BMF
  - androgen therapy for those with moderate-to-severe BMF if HSCT is contraindicated, or patient unwilling, ineligible, or has risk factors conferring a high transplant risk
  - if patients fail androgen therapy and not a candidate for HSCT, consider supportive care and/or cytokine therapy or enrollment in investigational protocols; see list of ongoing trials in patients with dyskeratosis congenita at clinicaltrials.gov
- in patients with dyskeratosis congenita who progress to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), consider
  - HSCT with or without prior induction chemotherapy or
  - enrollment in investigations protocols if patient is ineligible for HSCT; see list of ongoing trials in patients with dyskeratosis congenita at clinicaltrials.gov⁽¹⁾
management of pulmonary fibrosis
- mainstay of management is supportive care, including avoidance of potential toxic exposures and administration of supplemental oxygen^(1,2)
- limited evidence for pharmacologic treatment of pulmonary fibrosis; most evidence is related to idiopathic pulmonary fibrosis and not specific for patients with dyskeratosis congenita⁽¹⁾
- lung transplantation is shown to improve survival of end-stage pulmonary fibrosis; however many studies include patients with telomere-related pulmonary fibrosis without classic features of dyskeratosis congenita⁽¹⁾

Bone Marrow Failure

Hematopoietic Stem Cell Transplantation (HSCT)

General Considerations

HSCT is the only curative treatment for bone marrow failure and other hematologic complications from dyskeratosis congenita such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML); HSCT does not prevent development of pulmonary fibrosis or cancer, nor correct other nonhematopoietic aspects of the disease^(1,2,3)
severity of bone marrow failure contributes to timing and consideration of HSCT⁽¹⁾
- in mild-to-moderate bone marrow failure
  - monitor complete blood count and bone marrow until indication for treatment develops
  - consider referral to HSCT team if counts start to decline or for patients without human leukocyte antigen (HLA)-identical sibling to allow time for donor search
- in severe bone marrow failure
  - refer to HSCT team for HSCT planning
  - consider androgen therapy in patients ineligible for HSCT
if considering HSCT, refer patient to transplant center with experience in HSCT for dyskeratosis congenita⁽¹⁾
factors that may guide need for and timing of HSCT in patients with dyskeratosis congenita⁽¹⁾
- nature, severity, and predicted progression of hematologic manifestation
  - HSCT results are generally better for patients who present with bone marrow failure (compared to outcomes of patients presenting with myelodysplastic syndrome or leukemia)
  - historically, risk of graft failure is higher in patients who have received a higher number of red blood cell or platelet transfusions
- degree of HLA match and type of donor graft available
- patient’s age and overall clinical condition; HSCT results are generally better in younger patients
- degree of HLA match and type of donor available
- transplant physician’s recommendations and patient’s or parent’s decision to proceed

Indications/Contraindications for HSCT in Patients With Dyskeratosis Congenita

indications for HSCT in patients with dyskeratosis congenita⁽¹⁾
- absolute indications
  - severe cytopenias (hemoglobin < 8 g/dL, absolute neutrophil count < 0.5 × 10⁹/L, or platelets < 20 × 10⁹/L; or requiring red blood cell or platelet transfusions to prevent significant symptoms of low hemoglobin or platelets)
    - immunosuppressive therapy should not be used for idiopathic cytopenias, as it is unlikely to cure bone marrow failure in patients with dyskeratosis congenita
    - alternative treatment such as androgens or hematopoietic growth factors may be tried as temporizing measures, but not necessary if no contraindications to HSCT and suitable donor is available
  - high-risk MDS and AML (high-risk chromosomal abnormalities or bone marrow blast count > 5%)
- relative indications
  - moderate cytopenias (hemoglobin less than normal to ≥ 8 g/dL, absolute neutrophil count 0.5 to < 1 × 10⁹/L, or platelets 20 to < 50 × 10⁹/L)
    - consider HSCT if progression toward transfusion dependence and donor/graft with suitable degree of HLA compatibility is available
    - alternatively, may be reasonable to consider trial of androgen therapy prior to proceeding to HSCT
  - low-risk MDS (bone marrow dysplasia without chromosomal abnormalities or with low-risk chromosomal abnormalities)
    - if suitable donor is available, consider whether to proceed to HSCT rather than continue observation or trial androgen therapy
general contraindications for HSCT⁽¹⁾
- uncontrolled infections (fungal, bacterial, or viral)
- severe organ dysfunction, especially hepatic or pulmonary
- active pregnancy

Pretransplant Evaluation

comprehensive pretransplant evaluation in patients with dyskeratosis congenita should include⁽¹⁾
- past medical history
  - assess for factors that may complicate HSCT such as infections, blood transfusion requirements, and use of prior therapies such as androgens or hematopoietic growth factors
  - review history of other manifestations of dyskeratosis congenita such as neurologic, ophthalmologic, dental, gastrointestinal, pulmonary, hepatic, gynecologic/urologic, and oncologic conditions
  - obtain history of prior surgeries and medical treatments, allergies, and current medications, vitamins, supplements, and herbal therapies
- family history – any family members being considered as potential HSCT donors should have telomere length testing and genetic testing (if pathogenic variant is known) to determine risk and suitability as a donor
- complete systematic physical exam and other evaluations, including
  - examination for physical abnormalities associated with dyskeratosis congenita that may impact risk or treatment plan and establish baseline for each organ system
  - otolaryngology evaluation including laryngoscopy to examine for evidence of head and neck malignancy
  - neurological imaging to screen for brain cysts, white matter changes, and calcifications
  - pulmonary function testing, with measurement of oxygen saturation, diffusion capacity of the lung for carbon monoxide (DL_CO), and imaging for pulmonary fibrosis or arteriovenous malformations
  - liver function testing and evaluation for evidence of cirrhosis and varices
  - dual energy absorptiometry (DXA) scan to obtain baseline bone mineral density

Donor Considerations

compatibility of patient and donor for HSCT is determined primarily by degree of HLA matching between donor and recipient⁽¹⁾
patients, siblings, and parents should undergo HLA typing as soon as diagnosis is confirmed⁽¹⁾
matched sibling is generally considered an ideal donor⁽¹⁾
- benefits include high degree of shared genetic identity with patient, which reduces risk of graft-versus-host disease (GVHD), and availability for donation
- potential drawbacks include a sibling who may be a silent carrier of genetic mutation, who may have inherited short telomeres, or who may have hematopoietic stem cells that are not ideal for transplant
- all potential sibling donors should have complete blood count, telomere length testing, and genetic testing whenever possible
- in case of uncertainty, perform bone marrow exam to assess for hypocellularity or dysplasia
- unrelated donor may be considered if matched, related donor not available

Conditioning Regimens for Patients With Dyskeratosis Congenita

conditioning (also called preparative or cytoreductive) regimen is when a patient undergoes combination of chemotherapy, radiation, and/or immunosuppression with the aim of allowing engraftment of donor hematopoietic stem cells⁽¹⁾
- reduced-intensity conditioning regimens suggested for patients with dyskeratosis congenita; no current regimen is standard as this is an active area of clinical investigation
- high-intensity conditioning is fully myeloablative and are associated with increased toxicity (particularly acute and chronic pulmonary) and mortality in patients with dyskeratosis congenita
- combinations and dosages of agents can vary among transplant centers, though fludarabine phosphate is a major component of reduced-intensity conditioning regimen
67% overall survival reported in patients with dyskeratosis congenita having nonmyeloablative conditioning regimen prior to HSCT at median follow-up 26.5 months (level 3 [lacking direct] evidence)
- based on uncontrolled trial
- 6 patients with dyskeratosis congenita were treated with nonmyeloablative conditioning regimen for allogeneic HSCT
  - 5 patients had clinical diagnosis of dyskeratosis congenita that was confirmed by documentation of very short telomeres
  - 1 patient had dyskeratosis congenita-like presentation with bone marrow failure and very short telomeres, but no clinical features of mucocutaneous triad and no identifiable mutation in known dyskeratosis congenita gene
- nonmyeloablative regimen consisted of
  - alemtuzumab 0.2 mg/kg IV once daily from day -10 to day -6 (5 days)
  - cyclophosphamide 50 mg/kg IV as single dose on day -6
  - fludarabine 40 mg/m² IV once daily from day -6 to day -2 (5 days)
  - total body radiation 200 centigray (cGy) as single dose on day -1, delivered side-to-side
- all patients received cyclosporine and mycophenolate mofetil as prophylaxis against graft failure and GVHD
- 5 of 6 patients achieved complete donor engraftment after initial stem cell infusion
- overall survival 67% (4 patients) at median follow-up 26.5 months
- Reference – Bone Marrow Transplant 2011 Jan;46(1):98

Survival After HSCT

age > 20 years and use of donor other than matched sibling associated with poor overall survival in patients with dyskeratosis congenita treated with HSCT
- based on systematic review of observational studies
- systematic review of 36 observational studies (case series and cohort studies) evaluating factors associated with improved survival in 109 patients with dyskeratosis congenita who were treated with HSCT
- conditioning regimens varied
  - 86% received cyclophosphamide (most common agent used) and 99% received some form of alkylating agent or total body radiation
  - 71% received myeloablative regimens and those that received myeloablative regimens were treated earlier than those receiving reduced-intensity conditioning regimen
- median follow-up post HSCT was 2 years (range 0-20 years)
- predicted overall survival was 57% at 5 years and 23% at 10 years
- factors associated with poor overall survival after HSCT in multivariate analysis
  - age > 20 years at HSCT (odds ratio [OR] 3.3, 95% CI 1.6-6.9), consistent results in analysis of patients receiving HSCT after year 2000
  - use of donor other than matched sibling (OR 3.8, 95% CI 1.9-7.8), consistent results in analysis of patients receiving HSCT after year 2000
  - HSCT before year 2000 (OR 3.6, 95% CI 1.5-8.6)
- rates of adverse events
  - 37% had acute GVHD among 65 patients with available data
  - 43% had chronic GVHD among 51 patients with available data
  - 14% had pulmonary disease among 109 patients with available data
- Reference – Biol Blood Marrow Transplant 2016 Jul;22(7):1152 full-text
estimated 10-year overall survival of 30% reported in patients with dyskeratosis congenita treated with HSCT (level 3 [lacking direct] evidence)
- based on case series
- 34 patients aged 2-35 years (median age 13 years) with dyskeratosis congenita treated with HSCT were identified from data reported to Center for International Blood and Marrow Transplant Research (CIBMTR)
- 18 patients (53%) received related-donor HSCT (16 were HLA-identical sibling); 71% received stem cells from bone marrow
- 20 patients (59%) died, including 10 deaths that occurred during first 4 months after transplantation
- median follow-up of surviving patients was 46 months
- estimated overall survival was 70% at 1 year, 57% at 5 years, and 30% at 10 years
- rates of engraftment
  - 73% cumulative incidence of neutrophil recovery by day 28
  - 72% probability of platelet recovery by day 100 among 25 evaluable patients
- adverse events
  - acute GVHD developed in 24%; 100-day probability of acute GVHD was 24%
  - chronic GVHD developed in 32%; 3-year probability of chronic GVHD was 37%
  - Epstein-Barr virus associated lymphoproliferative disease, squamous cell carcinoma of the skin, and basal cell carcinoma of the skin developed in 1 patient each
- Reference – Biol Blood Marrow Transplant 2013 Aug;19(8):1238 full-text

Androgen Therapy

General Considerations

androgen therapy does not cure bone marrow failure but can improve blood counts during treatment^(1,2,3)
- normal levels of blood counts are not usually achieved, but improvements can result in independence from transfusional support
- peripheral blood counts respond adequately enough in approximately 50%-70% of patients with dyskeratosis congenita to obviate need for transfusion
- may take up to 3 months at a consistent dose to see a hematologic response
androgens are likely more effective in patients with some reserve of bone marrow, compared to those with severely depleted hematopoietic cellular content who may be or become refractory to androgen therapy⁽¹⁾
androgens do not prevent or delay progression to MDS or AML
patients with dyskeratosis congenita may exhibit increased sensitivity to side effects of androgens⁽¹⁾
CLINICIANS’ PRACTICE POINT: Despite androgen therapy being recommended for some patients, this is an off-label use for treatment of bone marrow failure in patients with dyskeratosis congenita.

Indications/Contraindications for Androgen Therapy

possible indications^(1,2)
- if HSCT is contraindicated (due to medical ineligibility or lack of suitable donor) or patient prefers not to undergo HSCT
- in presence of severe cytopenias, can be considered as an alternative treatment, but not necessary if aligns with patient preferences, no contraindications to HSCT, and suitable donor is available
- in presence of moderate cytopenias, may be reasonable to consider trial of androgen therapy prior to proceeding to HSCT
- if low-risk MDS, can consider trial of androgen therapy rather than observation or HSCT
contraindications to androgen therapy include use of some medications in combination with androgens^(1,3)
- prednisone, may cause avascular necrosis and loss of bone density (osteopenia and osteoporosis)
- granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), or erythropoietin, due to increased risk of splenic peliosis and rupture in patients with dyskeratosis congenita

Pretreatment Evaluation for Androgen Therapy

baseline testing prior to initiating androgen therapy^(1,3)
- complete blood count, liver function tests, and serum lipid profile
- liver/spleen ultrasound
- x-ray of hand to evaluate bone age in a growing child
- endocrine evaluation
- height and weight measurements

Drug Selection and Dosing Strategy

options include oxymetholone and danazol⁽¹⁾
danazol is a synthetic androgen derivative reported to cause less adverse effects than oxymetholone, specifically, less masculinizing effects^(1,2,3)
dosing strategy^(1,3)
- suggested initial dose
  - danazol – 2.5-5 mg/kg/day in children or 100-150 mg twice daily in adults; has been used at doses as high as 400 mg twice daily
  - oxymetholone – 0.5-1 mg/kg/day
- adjust dose based on response and monitoring for androgen-associated adverse effects
- once treatment started, may take up to 3 months at a consistent dose to see an increase in hemoglobin, platelets, and sometimes neutrophil counts
- after blood counts have stabilized, consider gradually decreasing dose over 2-6 months to lowest effective dose needed to maintain stable blood counts
blood counts do not generally reach normal values with androgen treatment, but may improve to the extent that a previously transfusion-dependent patient may no longer need red blood cell or platelet transfusion support⁽¹⁾
discontinue treatment if no response after an adequate trial (3-4 months) or consider switching to different androgen therapy (patients who do not respond to an initial androgen occasionally respond to a different one)⁽¹⁾

Monitoring

perform regular monitoring (and dose adjustment as needed) to achieve lowest effective dose and minimize or avoid toxicity⁽¹⁾
- regular monitoring by an endocrinologist for androgen-associated adverse effects impacting growth, bone age (early fusion of epiphyses), gonadal function, and lipid profile
- persistently abnormal cholesterol levels may be concern for future cardiovascular risk in patients on androgen therapy for ≥ 2-5 years; levels usually return to baseline within 3-6 months after discontinuing treatment
suggested frequency of monitoring^(1,2)

Table 6: Monitoring During Androgen Therapy

Parameter	Frequency
Complete blood count	Every 4-6 weeks until counts stable then every 2-3 months
Liver function tests	Every 6-12 weeks
Lipid profile	Every 6-12 months
Liver/spleen ultrasound	Every 6 months
Bone age	Every 6-12 months in a growing child
Endocrine evaluation	Annually
Height/weight measurement	Every visit

Efficacy

published literature on androgen use in dyskeratosis congenita is limited⁽¹⁾
androgen therapy associated with 69% hematologic response in patients with dyskeratosis congenita (level 3 [lacking direct] evidence)
- based on retrospective cohort study
- 44 patients (median age 16 years) with dyskeratosis congenita treated with androgens (16 patients, 36%) or no androgen therapy (28 patients, 63%)
- 69% hematologic response in patients treated with androgens; pretreatment vs. posttreatment
  - median hemoglobin 9.3 g/dL vs. 11.6 g/dL (p < 0.001)
  - median absolute neutrophil count (ANC) 0.55 × 10⁹/L vs. 1.51 × 10⁹/L (p < 0.01)
  - median platelet count 13.5 × 10⁹/L vs. 41.5 ×10⁹/L (p < 0.01)
- posttreatment telomere lengths were the same or shorter than pre-androgen measurements in 4 patients who responded to androgen therapy (and had telomere length measurements prior to) at median 2.6 years after androgen treatment
- no statistically significant difference in liver function between treated vs. not treated patients
- 2 patients who received G-CSF combined with androgens developed splenic peliosis leading to rupture
- Reference – Br J Haematol 2014 May;165(3):349 full-text
danazol reported to decrease rate of telomere shortening and improve hematologic parameters in patients with telomere diseases (level 3 [lacking direct] evidence)
- based on uncontrolled trial
- 27 patients (median age 41 years) with age-adjusted telomere length at or below first percentile and/or mutations in telomere maintenance and repair genes were treated with danazol 800 mg/day orally in 2 divided doses for 24 months
- all patients also had ≥ 1 low blood count and/or pulmonary fibrosis
- 3 patients with DKC1 mutation
- trial was terminated early because telomere attrition was reduced in first 12 patients evaluated at 24 months; all 12 patients achieved biological response, defined as telomere attrition rate of ≤ 96 base pairs/year
- hematologic response, defined as increase in hemoglobin level ≥ 1.5 g/dL (or transfusion independence or reduction in number of transfusions by > 50%), increase in platelet count ≥ 20 × 10⁹/L, or increase in neutrophil count 0.5 × 10⁹/L, occurred in
  - 79% of 24 patients evaluated at 3 months
  - 83% of 12 patients evaluated at 24 months
- Reference – N Engl J Med 2016 May 19;374(20):1922 full-text, editorial can be found in N Engl J Med 2016 May 19;374(20):1978, commentaries can be found in N Engl J Med 2016 Sep 15;375(11):1095, N Engl J Med 2016 Sep 15;375(11):1095, and N Engl J Med 2016 Sep 15;375(11):1095
- CLINICIANS’ PRACTICE POINT: Because the trial was terminated early, data on the persistence of the effects of danazol on telomere shortening is poorly characterized.

Adverse Effects

most common adverse effects reported with androgens include^(1,2)
- virilization (or masculinization in females and children), with facial and pubic hair growth, scalp hair loss, acne, penile/clitoral enlargement, priapism, and deepening of voice; likelihood of onset and degree of virilization are proportional to androgen dose
- behavioral changes such as aggression and mood swings
- decreased thyroid binding globulin
- liver toxicity (increased transaminase or bilirubin levels)
- alteration in blood lipid profile resulting in abnormalities of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels
- growth spurt in children, which may result in premature closure of epiphyses (growth plates) and short adult height
- liver adenomas, peliosis in spleen (especially when giving growth factors concomitantly) or liver, and rarely hepatocellular carcinoma

Hematopoietic Growth Factors

consider cytokines and investigational protocols in patients with severe bone marrow failure who are at high transplant risk and unresponsive to androgens⁽¹⁾
G-CSF and GM-CSF^(1,3)
- can improve blood counts temporarily and may be useful in patients with persistent neutropenia (absolute neutrophil count < 1 × 10⁹/L), especially in presence of recurrent or serious infections
- may increase risk for proliferation of a malignant clone, resulting in malignant transformation
- concurrent administration with androgen therapy is contraindicated due to increased risk for splenic peliosis and rupture
thrombopoietin receptor agonists not recommended outside of a clinical trial; eltrombopag has not been studied in patients with dyskeratosis congenita⁽¹⁾

Blood Products

some patients may need red blood cell and platelet transfusion support before definitive treatment can be started or becomes effective, or if other measures have failed⁽¹⁾
all blood products should be irradiated and leuko-depleted prior to administration⁽³⁾
in patients who are candidates for HSCT⁽³⁾
- avoid or minimize transfusions
- if blood transfusion is necessary, avoid using family members as blood donors to reduce chances of sensitization
red blood cell transfusion⁽¹⁾
- indicated in patients with anemia to maintain normal hemoglobin and quality of life
- monitor for iron overload using serum ferritin, T2-weighted magnetic resonance imaging of heart and liver, or other relevant tests
- if necessary, start treatment for iron overload with iron chelators such as deferoxamine or deferasirox
platelet transfusion⁽¹⁾
- possible indications in patients with thrombocytopenia
  - presence of mucosal bleeding (aminocaproic acid may be used as adjunctive therapy in appropriate patients)
  - undergoing invasive procedures
- avoid medications that inhibit platelet function, such as nonsteroidal anti-inflammatory drugs and aspirin
- advise patients against performing activities with high risk of trauma (such as contact sports)

Vaccinations

progressive immune deficiency, resulting in increased susceptibility to life-threatening infections, is common in dyskeratosis congenita (especially Hoyeraal-Hreidarsson syndrome)⁽¹⁾
recommended vaccinations include⁽¹⁾
- influenza vaccination annually, especially in patients with pulmonary involvement
- human papillomavirus (HPV) vaccine series, preferably before becoming sexually active
hypogammaglobulinemia sometimes associated with dyskeratosis congenita may decrease effectiveness of some vaccinations⁽¹⁾

Hormonal Therapy for Excessive Menstrual Bleeding

in women with excessive menstrual bleeding in setting of severe thrombocytopenia or bone marrow failure, consider oral contraceptives⁽¹⁾
- for mild-to-moderate bleeding
  - low-dose combined oral contraceptive usually adequate
  - low-dose contraceptives can be given via transdermal patch, especially in women with elevated liver enzymes or poor tolerance for oral medication
- for severe bleeding
  - high-dose oral contraceptives (ethinyl estradiol ≥ 50 mcg) or injectable estrogens (IV Premarin 25 mcg every 6 hours for 24 hours) can be used
  - maintain higher doses until bleeding stops and then switch to medication that can be used long-term, such as low-dose combined oral contraceptive or leuprolide
- high-dose estrogen decreases risk of endometrial atrophy but long-term use can result in excessive bleeding
in women undergoing transplant and with excessive menstrual bleeding, leuprolide acetate given as intramuscular injection prior to undergoing HSCT can suppress menstruation⁽¹⁾
- consider risk of bruising or bleeding at injection site; severe thrombocytopenia may be a relative contraindication in some patients
additional treatment with hormone replacement may be beneficial in women who have intolerable hypoestrogenic side effects such as hot flashes or vaginal dryness⁽¹⁾

Pulmonary Fibrosis

Considerations

pulmonary fibrosis associated with dyskeratosis congenita may occur⁽¹⁾
- early in life, following onset of bone marrow failure (BMF), and may be accelerated by exposure to conditioning regimens of transplantation
- as first life-threatening complication in patients > 30 years old
- Reference – J Blood Med 2014;5:157 full-text
in patients with pulmonary fibrosis manifesting after hematopoietic stem cell transplantation (HSCT), diagnosis may be challenging due to nonspecific clinical findings and histopathology, and range of other etiologies⁽¹⁾

Supportive Care

supportive care is mainstay of management as there is limited evidence for pharmacological treatment and many patients are not candidates for lung transplantation⁽¹⁾
can provide supplemental oxygen⁽²⁾
avoidance of potential environmental, iatrogenic, or chemical exposures such as⁽¹⁾
- avoidance of primary and secondary tobacco smoke
  - strongly advise against smoking
  - provide multidisciplinary support to patients, which may include referral to support groups and other counseling strategies
- minimizing cytotoxic medications and radiation if included in conditioning regimens for hematopoietic stem cell transplantation
  - use aggressive lung shielding if ionizing radiation required
  - avoid busulfan due to pulmonary toxicity and other medications that have pulmonary toxicities when possible
  - avoid fibrogenic medications, such as nitrofurantoin and amiodarone, when possible
- using regional anesthesia and avoiding high partial pressure oxygen with elective surgery when feasible, to decrease risk of triggering alveolar epithelial injury
- using respiratory protective equipment in patients at increased risk of exposure to occupational or environmental hazards, if they cannot be avoided
- treating respiratory infections promptly
- offering immunizations against respiratory tract pathogens according to standard practice

Medications

there is limited evidence for pharmacological treatment; available evidence is not specific for patients with dyskeratosis congenita⁽¹⁾
short telomere syndrome-associated pulmonary disease responds poorly to standard treatments such as corticosteroids and bronchodilators⁽²⁾
2 medications (pirfenidone and nintedanib) are FDA approved for use in adults with idiopathic pulmonary fibrosis, based on decreased rates of lung function decline in treated patients⁽¹⁾
- have not been shown to improve survival
- benefits and toxicities are unknown in patients with dyskeratosis congenita as the approval trials did not explicitly include or exclude genetically defined pulmonary fibrosis subsets
- have not been tested and are not approved for children
- have not been tested in patterns of idiopathic interstitial lung disease other than idiopathic pulmonary fibrosis
pirfenidone (Esbriet)
- pirfenidone granted fast track, priority review, orphan product, and breakthrough designations
- use not recommended in patients with severe liver problems, end-stage kidney disease, or who require dialysis
- Reference – FDA Press Release 2014 Oct 15
- pirfenidone (Esbriet) approved in Europe (March 3, 2011) and as Pirespa in Japan (October 16, 2008) and South Korea (July 12, 2011)
nintedanib (Ofev)
- nintedanib granted fast track, priority review, orphan product, and breakthrough designations
- use not recommended in patients with moderate-to-severe liver problems, and women should not become pregnant while taking nintedanib due to risk of birth defects or fetal death
- Reference – FDA Press Release 2014 Oct 15

Lung Transplantation

lung transplantation is only treatment shown to improve survival of end-stage pulmonary fibrosis; many studies include patients with telomere-related pulmonary fibrosis without classic features of dyskeratosis congenita⁽¹⁾
factors to consider when determining candidacy for lung transplant⁽¹⁾
- having undergone hematopoietic stem cell transplant (lung transplant is often a high-risk procedure as they have already have evidence of nonpulmonary end organ damage)
- comorbidities
- risk of potential complications
- experience of transplant center
bilateral lung transplant reported to resolve respiratory symptoms in case report of 14-year-old Asian male with dyskeratosis congenita who developed pulmonary fibrosis 7 years after hematopoietic stem cell transplant for aplastic anemia (BMC Blood Disord 2011 Jun 15;11:3 full-text)
efficacy of lung transplant in patients with pulmonary fibrosis and telomerase mutation, but not specifically dyskeratosis congenita
- high risk of hematologic complications reported in 31 patients with idiopathic pulmonary fibrosis carrying telomerase mutations treated with lung transplantation (level 3 [lacking direct] evidence)
  - based on 3 case series
  - 9 patients with pulmonary fibrosis and telomerase complex mutations were treated with lung transplant and evaluated for median follow-up 1.2 years
    - median age at diagnosis of pulmonary fibrosis was 50 years, median age at transplant was 52 years
    - median survival after transplantation 214 days
    - prior to transplantation
      - 7 patients with thrombocytopenia
      - 1 patient with anemia
    - hematologic complications post transplantation
      - 6 patients developed myelodysplasia and/or bone marrow failure
      - anemia was observed in 9 patients
      - neutropenia was observed in 3 patients
    - Reference – J Heart Lung Transplant 2015 Apr;34(4):538
  - 8 patients with pulmonary fibrosis and telomerase mutation or telomere syndrome were treated with lung transplant and evaluated
    - median age at diagnosis of pulmonary fibrosis was 47 years, median age at transplant was 52 years
    - at median follow-up 1.9 years
      - 88% survival (7 patients)
      - 4 patients had no rejection, 4 had evidence of minimal rejection (including 1 with transient evidence of moderate rejection)
      - hematologic complications were most common morbidity
        
        all patients required adjustment of immunosuppressive regimen (most were only able to tolerate 2-drug regimen)
        
        7 patients required platelet transfusion support
      - 4 patients required renal replacement therapy in first 2 weeks post transplant due to acute renal failure and acute tubular necrosis
      - 3 patients had gastrointestinal bleeding requiring red blood cell transfusion support
    - Reference – J Heart Lung Transplant 2015 Oct;34(10):1318 full-text
  - 14 patients (median age 60 years) with pulmonary fibrosis and telomerase mutations were treated with lung transplantation and evaluated
    - 12 patients (86%) had bilateral lung transplant
    - at mean follow-up 3.2 years
      - 93% survival (13 patients)
      - 10 patients had leukopenia and 5 did not tolerate lymphocyte antiproliferative agents
      - 6 patients developed recurrent lower respiratory tract infections
      - 7 patients developed acute cellular rejection, 4 patients developed chronic lung allograft dysfunction
      - 8 patients developed ≥ 1 episode of acute renal failure
      - 10 patients developed chronic renal insufficiency
      - 3 patients developed cancer
    - Reference – J Heart Lung Transplant 2015 Oct;34(10):1318 full-text

Consultation and Referral

Multidisciplinary Care

if diagnosis of pulmonary fibrosis is suspected, refer to specialist with clinical expertise in this area prior to invasive testing⁽¹⁾
appropriateness of other referrals based on presentation and management⁽¹⁾
- dental team if patient is undergoing hematopoietic stem cell transplant (HSCT)
- orthopedic specialist if skeletal complications present
- endocrinologist in patients with significant exposure to corticosteroids, bone fracture history, immobility, hypogonadism, or hormone deficiencies
- women’s health issues
  - adolescent medicine specialist or pediatric endocrinologist if menses does not occur within 3 years after breast buds develop or by age 16 years
  - maternal-fetal medicine specialist if pregnancy occurs
  - reproductive endocrinologist or fertility specialist if considering fertility preservation prior to initiating cancer treatment or HSCT
- specialty mental health services if indicated based on routine screening for neuropsychiatric conditions
offer referrals to appropriate counseling and other resources, including support groups, to provide adequate psychosocial support⁽¹⁾

Genetic Counseling

genetic counseling for patient and their family members is an integral component of management of dyskeratosis congenita⁽¹⁾
offer genetic counseling, including discussion of potential risks to offspring and reproductive options to patients who are affected, are carriers, or are at risk of being carriers⁽³⁾
genetic counseling can provide improved understanding of dyskeratosis congenita; discussion should include⁽¹⁾
- family history
- genetic information, both general and specific to dyskeratosis congenita
- genetic testing
  - testing options and process
  - risks, benefits, and limitations of testing
  - interpretation of results
- risk assessment for other family members
- family planning
- psychological and social issues
- identification of support for families
genetic risk assessment and use of family history and genetic testing is used to clarify genetic status for family members^(1,3)

Table 7: Patterns of Inheritance and Risk to Family Members

Relationship to Proband	X-linked	Autosomal Dominant	Autosomal Recessive
Parents	Father: will not be affected by mutation; no testing neededMother: may or may not be a carrier (dependent on number of male offspring affected)	May be affected, but may be asymptomatic; perform genetic testing and if no pathogenic variant identified, telomere length testing	Heterozygous carriers; may be asymptomatic
Siblings	If mother has mutation, 50% chance of inheritanceMales who inherit pathogenic variant will be affectedFemales who inherit pathogenic variant will be carriers (usually not affected)	If parents are affected, 50% chance of inheritance if parents are affected	At conception:50% chance of inheriting 1 pathogenic variant25% chance of inheriting none or both pathogenic variants
Offspring	Affected males will transmit mutations to:All daughters (carriers); usually not affectedNone of their sons	50% chance of inheritance	Heterozygous carriers
Others	Maternal aunts and their offspring may be at risk of being carriers	Depends on genetic status of parents of proband	Each sibling of proband’s parents has 50% chance of being a carrier

Reproductive Counseling

provide counseling about safe sex practices to limit/avoid exposure to sexually transmitted infections, important because of impaired immune response in many patients with dyskeratosis congenita⁽¹⁾
family planning^(1,3)
- optimal timing for determining genetic risk, carrier status, and discussion of availability of prenatal testing is prior to pregnancy
- prenatal testing and preimplantation genetic diagnosis are possible if the pathogenic variant has been identified
- in patients undergoing HSCT
  - discuss likelihood of infertility after HSCT
  - discuss options regarding sperm banking and cryopreservation pre-HSCT and post-HSCT in vitro fertilization
management of pregnant women⁽¹⁾
- maternal-fetal medicine specialist should monitor prenatal health of baby and mother as women with dyskeratosis congenita are at increased risk of pregnancy complications related to low hemoglobin and platelet counts
- discontinue androgens due to risk of masculinization of fetus
- bone marrow failure may worsen during pregnancy and transfusion may be needed because of low platelet counts

Other Management

Lifestyle Management

provide counseling on healthy lifestyle and avoidance of harmful habits such as smoking and alcohol consumption, which may accelerate lung and liver disease^(1,3)

Oral Hygiene

recommended good oral hygiene practices⁽¹⁾
- brushing teeth 2-3 times daily using fluoridated toothpaste and flossing at least once daily to prevent tooth decay
- biannual dental checkups and cleanings to monitor for presence of oral pathology and prevent development of significant dental decay and gum disease
- encouraging dietary habits that promote oral health, such as
  - limiting foods that are cariogenic or that lower salivary pH (which hastens demineralization of tooth surfaces)
  - ensuring sufficient calcium and vitamin D intake for appropriate bone growth and mineralization

Skin and Nail Care

skin and nail care⁽¹⁾
- approaches for managing fragile nails may include
  - reduce excessive exposure to water, detergents, and prolonged hand washing
  - avoid long-term use of artificial nails
  - use of nail polishes and lacquers, which can help strengthen brittle nails
- approaches to maintain skin health may include
  - use of moisturizer daily, after bathing, to maintain skin’s natural water content
  - avoiding abrasive or drying soaps and detergents
  - adequate water intake to stay well-hydrated
  - annual full body skin exam by dermatologist
- approaches to prevent skin cancer include
  - limiting sun exposure through
    - limiting outdoor time during hours of peak sun exposure (between 10 AM and 4 PM)
    - regular use of sunscreen or sunblock with broad ultraviolet A and B protection and sun protection factor (SPF) ≥ 30 when outdoors, and use of daily moisturizing lotion with sunblock
    - wearing hats and sun-protective clothing when outdoors
  - avoiding tanning beds

Follow-up

Monitoring of Bone Marrow Failure

for specific monitoring during or after treatment, see
- surveillance after hematopoietic stem cell transplantation (HSCT)
- monitoring during androgen therapy
monitor blood counts and bone marrow to assess progression of disease; use trajectory of decline to determine frequency of monitoring⁽¹⁾
- children generally have more rapidly progressive disease and more frequent monitoring is indicated
- older patients may have more stable hematological parameters and less frequent monitoring may be appropriate
general guidelines for monitoring^(1,3)
- if normal or mildly low blood counts and no cytogenetic abnormality
  - complete blood count (CBC)
    - every 4-6 months to determine stability of blood counts
    - if blood counts remain stable, annual monitoring may be adequate
  - perform bone marrow aspirate, biopsy, and cytogenetic studies if blood count abnormalities develop or annually
- if blood counts are falling or rising
  - exclude infection
    - blood counts may drop significantly after infection in patients with limited bone marrow reserve
    - blood counts often return to baseline within a few weeks of recovery from infection
  - if blood counts progressively changing without a clinically apparent underlying cause, bone marrow morphology and cytogenetic evaluation may be indicated
- if patient has clonal cytogenetic abnormality
  - more frequent monitoring of CBC and bone marrow may be indicated, depending on stability of blood counts and bone marrow findings
  - bone marrow exam with cytogenetics and fluorescence in situ hybridization (FISH)studies may be needed every 4-6 months to identify clonal progression or evolution, or morphologic myelodysplastic syndrome

Monitoring for Pulmonary Fibrosis

there are no clinical trials evaluating utility of screening protocols for pulmonary fibrosis in dyskeratosis congenita⁽¹⁾
in children who received hematopoietic stem cell transplantation, there should be increased suspicion for pulmonary fibrosis⁽¹⁾
- decision to repeat testing should be weighed against patient’s respiratory symptoms, physical exam, and level of impairment at baseline
- optimal frequency of repeat testing is not known, though regular monitoring may be warranted because of higher frequency of pulmonary fibrosis in this population
- if pulmonary fibrosis is suspected, refer patient to pulmonologist/specialist prior to performing chest imaging or more invasive procedures
- computed tomography of chest should not be used as routine screening tool in pediatric patients (to limit exposure to ionizing radiation)
in asymptomatic children⁽¹⁾
- risk of existing significant pulmonary fibrosis is low
- no consensus on optimal method for establishing clinical baseline or subsequent monitoring
in asymptomatic adults⁽¹⁾
- appropriate interval for repeat testing not established
- potential benefits of routine, frequent, repeat imaging should be weighed against risks of radiation exposure
- development of suspicious new or worsening respiratory symptoms should prompt consultation and evaluation with pulmonologist

Monitoring for Malignancy

surveillance for malignancy (especially dermatological and ear, nose, and throat exams) is important^(1,2)
- most cancers present at ages younger than expected and occur more frequently than predicted
- early detection can allow for complete surgical resection of lesions and avoid need for potentially harmful adjuvant therapy
in addition to the same cancer screening recommendations as the general population, suggested cancer screening intervals to consider for patients with dyskeratosis congenita⁽¹⁾

Table 8: Cancer Screening

Type of Cancer	Age to Start Screening	Screening Method	Screening Frequency
Liver	Infancy	Liver enzymes, ultrasound	At least annually*
Skin	Infancy	Dermatology exam	At least annually*
Leukemia	Infancy	CBC, bone marrow aspirate, biopsy	At least annually*
HNSCC	10 years	Oral exam during dental visits, nasolaryngoscopy	Oral exam every 6 months; ENT evaluation every 6-12 monthsMore frequently in presence of histologically confirmed oral dysplasia or history of oral cancer
Rectal	12 years	Physical exam, stool blood	At least annually*
Gynecologic	16 years or menarche	Gynecologic exam, Pap smear, HPV testing	At least annually*
Penile	10 years for physical exam to look for phimosis or lichen planus; approximately 16 years for HPV testing	Physical exam, HPV testing	At least annually*
Esophageal	20 years	Esophagoscopy	At least annually*
Lung	40 years	As clinically indicated: chest x-ray, lung function tests	At least annually*
Breast	According to guidelines for otherwise healthy women
Other	Symptom onset	Depends on symptoms

Citation: Abbreviations: CBC, complete blood count; ENT, otolaryngologist; HNSCC, head and neck squamous cell carcinoma; HPV, human papillomavirus.* More frequently if abnormalities are detected.

Additional Routine Follow-up

monitor for clinical features of dyskeratosis congenita, which may develop over time⁽¹⁾
- regular physical exams are warranted
- periodic ophthalmologic evaluations should be part of routine care
- liver function tests annually, depending on patient’s specific clinical manifestations
- routine screening for neuropsychiatric conditions
- dual energy absorptiometry (DXA) scan to assess bone mineral density
  - perform at or around age 14 years to obtain baseline bone mineral density, if not already performed
  - in older patients with dyskeratosis congenita without corticosteroid exposure, fracture history, or hormone deficiency may be monitored according to age-specific guidelines
- serum calcium, magnesium, and 25-hydroxyvitamin D levels in patients with low bone mineral density and patients who have undergone hematopoietic stem cell transplant

Complications and Prognosis

Complications

bone marrow failure^(1,2)
- the most severe and commonly occurring complication
- reported in approximately 80% of patients with dyskeratosis congenita
- isolated cytopenias may be seen in patients with mutations in TERC or TERT
- most significant cause of mortality in patients with dyskeratosis congenita (60%-70% of deaths)
malignancy^(1,2)
- hematological
  - myelodysplastic syndrome (MDS)
    - patients with dyskeratosis congenita have > 2,500-fold higher risk of MDS over the general population
    - median age at MDS diagnosis 35 years, significantly younger than for sporadic cases (> 60 years)
  - acute myeloid leukemia (AML)
    - patients with dyskeratosis congenita have 200-fold higher risk of AML over the general population
  - no standard effective therapy other than hematopoietic stem cell transplantation (HSCT) has been established for MDS or AML associated with dyskeratosis congenita
  - patients should be referred for HSCT with or without prior induction chemotherapy
  - experimental phase I or II clinical trials may be considered for patients ineligible for HSCT; see list of ongoing trials in patients with dyskeratosis congenita at clinicaltrials.gov
- solid tumor^(1,2,3)
  - malignancy reported in 30%-50% of patients with dyskeratosis congenita by age 40 years old⁽²⁾
  - in patients < 50 years old without bone marrow failure, solid tumors (head and neck squamous cell cancer [HNSCC] or anogenital adenocarcinoma) may be first presenting manifestation of dyskeratosis congenita⁽³⁾
  - types of malignancies^(1,2)
    - HNSCC
      - the most frequently reported solid organ tumors (40%) in patients with dyskeratosis congenita
      - 70-fold increased risk over the general population
      - median age of diagnosis of HNSCC in patients with dyskeratosis congenita is 32 years, considerably younger than sporadic cases (62 years)
      - more common in oral cavity than the oropharynx compared with HNSCC in general population
      - often arises in areas of existing leukoplakia
      - early diagnosis and surgical management of oral dysplasia/HNSCC is extremely important in reducing patient morbidity
      - Reference – Blood 2017 Nov 23;130(21):2257 full-text
    - non-head and neck cancers
      - most commonly stomach, anorectal, and skin squamous cell carcinomas
      - less common are hepatocellular carcinoma, lung cancer, gastrointestinal malignancies and Hodgkin disease
pulmonary fibrosis⁽²⁾
dermatologic complications⁽¹⁾
ophthalmologic complications⁽¹⁾
oral complications, including oral leukoplakia and oral lichen planus^(1,2) which typically occurs in patients < 50 years old and has increased risk of transformation to malignant HNSCC
dental complications^(1,2)
endocrine complications⁽¹⁾
skeletal complications^(1,2)
vascular complications including
- gastrointestinal telangiectasias of stomach, liver, and intestines ⁽¹⁾
  - gastrointestinal bleeding may occur regardless of underlying cause
  - patients may also develop porto-systemic varices due to portal hypertension resulting from noncirrhotic liver disease, or hepatic fibrosis
- pulmonary vascular malformations including⁽¹⁾
  - hepatopulmonary syndrome
  - portal hypertension from noncirrhotic liver disease, or hepatic fibrosis
  - pulmonary arteriovenous malformations (AVMs)
gastrointestinal complications^(1,2)
genitourinary complications, including increased risk of malignancy (especially anogenital cancers in men)⁽¹⁾
hepatic complications, including^(1,2)
- hepatic cirrhosis
- hepatocellular carcinoma
neurological complications^(1,2)
exposure to ionizing radiation for diagnostic (very low intensity), interventional (moderate intensity), or therapeutic (high intensity) purposes may cause⁽¹⁾
- cell death or injury in a population of cells due to low threshold for tissue reactions
- long-term complications including DNA damage or development of cancer (stochastic effects)
immunologic complications (especially in patients with Hoyeraal-Hreidarsson [HH] syndrome, who exhibit progressive immune deficiency manifesting as increased susceptibility to life-threatening infections)⁽¹⁾
gynecological/reproductive complications
- dyskeratosis congenita and related telomere biology disorder associated with increased risk of cesarean birth among pregnant patients compared to general population in the United States
  - based on cohort study
  - 39 female patients aged 10-81 years (median age 33 years) with dyskeratosis congenita and related telomere biology disorder from National Cancer Institute’s Inherited Bone Marrow Failure Syndrome (IBMFS) study between 2002 and 2019 were evaluated
    - 67% had bone marrow failure at median age 18 years
    - 31% received hematopoietic cell transplantation at median age 25 years for severe aplastic anaemia or acute myeloid leukemia
  - all patients had menarche at normal age (median age 12 years)
  - among 77% with detailed menstrual history, 43% reported heavy periods
  - 23% had natural menopause at median age 49 years
  - 18% had surgical menopause following hysterectomy with oophorectomy for endometriosis, pelvic varicosities, cervical intraepithelial neoplasia, or uterine prolapse
  - fertility and pregnancy outcomes
    - 67% had ≥ 1 pregnancy (median age at first pregnancy 25 years); total number of pregnancies were 80
    - 64% gave birth to ≥ 1 live-born child (51 live births in total, including 2 sets of twins)
    - cesarean birth in 44% of patients, compared to 18.5% in general population in the United States (p = 0.001)
    - preterm birth (≤ 36 weeks gestation) in 16% of pregnancies resulting in live births, compared to 9.5% in general population in the United States (not significant)
    - 35% of pregnancies ended in miscarriage or midtrimester losses, compared to 10%-20% in general population in the United States (p = 0.02 to p < 0.0001)
    - 15.4% with infertility due to endometriosis, scarred or blocked fallopian tubes, or anovulation received follicle-stimulating agents or had in vitro fertilization or intrauterine insemination
  - Reference – Br J Haematol 2021 Jun;193(6):1238 full-text

Prognosis

median age of survival reported to be
- 44 years for classic dyskeratosis congenita
- 5 years for Hoyeraal-Hreidarsson syndrome
- 11 years for Revesz syndrome
- Reference – Hematol Oncol Clin North Am 2009 Apr;23(2):215 full-text
causes of mortality in patients with dyskeratosis congenita include⁽²⁾
- bone marrow failure in 60%-70%
- pulmonary fibrosis in 10%-15%
autosomal dominant disease associated with longer survival compared to autosomal recessive/X-linked disease or disease due to TINF2 variant in children and adults with telomere biology disorder
- based on cohort study
- 231 children and adults (median age at diagnosis 19 years, 62% male, 74% White) with telomere biology disorder in National Cancer Institute’s Inherited Bone Marrow Failure Syndrome (IBMFS) study between January 2002 and May 2019 were followed for median 5.2 years
  - 86.1% had dyskeratosis congenita
  - 10% had Hoyeraal-Hreidarsson syndrome
  - 2.6% had Revesz syndrome
  - 1.3% had Coats plus syndrome
- inheritance pattern
  - 48.5% had autosomal dominant disease (without TINF2 variant)
  - 27.3% had autosomal recessive/X-linked disease
  - 10.8% had TINF2 variant
  - 13.4% had unknown genotype
- 30.3% had hematopoietic cell transplantation
- overall mortality was 42% at last follow-up
- severe bone marrow failure in
  - 48.1% overall
  - 29.5% among patients with autosomal dominant disease
  - 69.8% among patients with autosomal recessive/X-linked disease (p < 0.01 vs. autosomal dominant disease)
  - 76% among patients with TINF2 variant (p < 0.01 vs. autosomal dominant disease)
  - 48.4% among patients with unknown genotype
- median overall survival
  - 52.8 years overall
  - 64.9 years among patients with autosomal dominant disease (p < 0.01 vs. autosomal recessive/X-linked disease or TINF2 variant)
  - 31.8 years among patients with autosomal recessive/X-linked disease (not significant vs. TINF2 variant)
  - 37.9 years among patients with TINF2 variant
  - 27.8 years among patients with unknown genotype
- median hematopoietic cell or solid organ transplant-free survival was 45.3 years
- Reference – Blood 2022 Mar 24;139(12):1807 full-text

Prevention and Screening

Screening

Screening of at-risk relatives

telomere length testing or molecular genetic testing (if known pathogenic variant[s]) indicated if^(2,3)
- relative has signs or symptoms suggestive of dyskeratosis congenita
- relative is being considered as potential hematopoietic stem cell transplant donor, as he or she may share same mutation without clinical manifestations
- relative is apparently asymptomatic, to identify as early as possible those who would benefit from initiation of treatment and preventive measures

Prenatal/preimplantation screening

if the pathogenic variant has been identified, preimplantation or prenatal diagnosis are possible^(1,3)
- prenatal testing with chorionic villus sampling or amniocentesis
- in vitro fertilization with preimplantation genetic diagnosis

Guidelines and Resources

Guidelines

no relevant guideline for Dyskeratosis congenita found 2018 Feb 22 on systematic search of MEDLINE (using guidelines limiter) and National Guideline Clearinghouse

Review Articles

review can be found in Mutat Res 2012 Feb 1;730(1-2):43 full-text
review can be found in Hematology Am Soc Hematol Educ Program 2011;2011:480
review can be found in Int J Hematol 2010 Oct;92(3):419
review can be found in Hematol Oncol Clin North Am 2009 Apr;23(2):215 full-text
review on allogenic hematopoietic stem cell transplantation for dyskeratosis congenita can be found in Curr Opin Hematol 2016 Nov;23(6):501
review on inherited bone marrow failure syndromes and considerations before and after allogenic hematopoietic stem cell transplantation can be found in Blood 2017 Nov 23;130(21):2257 full-text
review on biology and management of dyskeratosis congenita and related telomere biology disorders can be found in Expert Rev Hematol 2013 Jun;6(3):327
review on genetics of dyskeratosis congenita can be found in Cancer Genet 2011 Dec;204(12):635 full-text
review on diagnosis and treatment of dyskeratosis congenita can be found in J Blood Med 2014;5:157 full-text
review on bone marrow failure and telomeropathies can be found in Blood 2014 Oct 30;124(18):2775 full-text
review on cancer in dyskeratosis congenita can be found in Blood 2009 Jun 25;113(26):6549 full-text, editorial can be found in Blood 2009 Jun 25;113(26):6502

MEDLINE Search

to search MEDLINE for (Dyskeratosis congenita) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis

Patient Information

handout from National Organization for Rare Disorders
information from Contact for Families with Disabled Children

References

General References Used

The references listed below are used in this DynaMed topic primarily to support background information and for guidance where evidence summaries are not felt to be necessary. Most references are incorporated within the text along with the evidence summaries.

Savage SA, Cook EF, eds. Dyskeratosis Congenita and Telomere Biology Disorders: Diagnosis and Management Guidelines PDF. 1st ed. New York, NY: Dyskeratosis Congenita Outreach, Inc.; 2015 .
Barbaro PM, Ziegler DS, Reddel RR. The wide-ranging clinical implications of the short telomere syndromes. Intern Med J. 2016 Apr;46(4):393-403.
Savage, SA. Dyskeratosis Congenita. GeneReviews 2016 May 16.