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Telomeropathies or telomere biology disorders (TBDs) are a group of rare diseases characterised by altered telomere maintenance. Most patients with TBDs show pathogenic variants of genes that encode factors involved in the prevention of telomere shortening. Particularly in adults, TBDs mostly present themselves with heterogeneous clinical features that often include bone marrow failure, hepatopathies, interstitial lung disease and other organ sites. Different degrees of severity are also observed among patients with TBDs, ranging from very severe syndromes manifesting themselves in early childhood, such as Revesz syndrome, Hoyeraal-Hreidarsson syndrome, and Coats plus disease, to dyskeratosis congenita (DKC) and adult-onset "cryptic" forms of TBD, which often affect fewer organ systems. Overall, the most relevant clinical complications of TBD are bone marrow failure, lung fibrosis, and liver cirrhosis. In this review, we summarise recent advances in the management and treatment of TBD and provide a brief overview of the various treatment approaches.

Background: Revesz syndrome is a rare type of the dyskeratosis congenita spectrum disorder that is characterized by nail dystrophy, oral leukoplakia, and abnormal skin pigmentation. The retinal features are similar to those of exudative retinopathy with avascular areas of the peripheral retina. There are only a few publications describing patients with Revesz syndrome who underwent ocular treatments for the retinal complications. We report a Case of Revesz syndrome with bilateral retinal detachments that were successfully reattached by pars plana vitrectomy. Observations: A 3-year-old Japanese girl with Revesz Syndrome had progressive vitreal hemorrhages and tractional retinal detachments in both eyes. She underwent pars plana vitrectomy with lensectomy on both eyes. A retinal attachment with vision improvement was achieved by a single surgery for the right eye and after repeated surgeries for the left eye. Postoperative electroretinographic (ERG) examinations of the right eye showed a negative type ERG with the b-wave/a-wave ratio

This report describes 2 cases of dyskeratosis congenita in patients with progressive pulmonary diseases who required urgent living-donor lung transplantations. In the first case, a 13-year-old boy underwent bone marrow transplantation for aplastic anemia at age of 6 years. Severe pulmonary right-to-left shunting and fibrosis developed, and his condition deteriorated with acute fibrosis exacerbation and increased intrapulmonary shunt. He underwent lung transplantation and recovered uneventfully. In the second case, a 3-year-old girl with Revesz syndrome underwent bone marrow transplantation for refractory cytopenia. At 6 years of age, she had progressive hypoxia and a brain abscess. Her respiratory condition worsened, and she recovered uneventfully after urgent lung transplantation.

Purposes To inform about a case of Revesz syndrome (RS) with initial ophthalmological symptomatology of severe proliferative vitreoretinopathy of the left eye (LE). After the aplastic anemia had developed, RS was established. The exudative retinopathy was successfully treated with photocoagulation on the right eye (RE). Background RS is characterized by fatal bone marrow failure, exudative retinopathy, neuroradiographic abnormalities, neurodevelopmental delay and skin abnormalities. Non-treated exudative retinopathy leads to blindness. Methods We report ophthalmological findings as follows: fundus photography and fluorescein angiography (FA) acquired by examinations under general anesthesia in patient with RS. Results of genetic tests helped to establish the diagnosis. Results Two‑year old Caucasian male was examined due to total retinal detachment on LE and signs of chorioretinal scarring on RE. In preoperative screening, thrombocytopenia was detected; later, severe pancytopenia developed. Considering the hematological findings and clinical appearance, we suspected RS, which was confirmed by genetic tests. We found a pathogenic mutation in gene TINF2 (variant c.865C>T;p.Pro289Ser) in a mosaic state with autosomal dominant mode of inheritance. This mutation has not been described in RS yet. Blind LE was enucleated because of dolorous neovascular glaucoma. FA of RE shows excessive areas of capillary nonperfusion with vascular abnormalities and exudation. After the photocoagulation, the visual acuity (VA) on RE remains 0.9 at the age of 7 years. Conclusions RS is an extremely rare condition. The initial symptomatology could be ophthalmological or hematological. The positive finding of TINF2 gene mutation helped in establishing the correct diagnosis. The ischemic retinopathy was successfully treated by photocoagulation (Fig. 6, Ref. 6). Text in PDF www.elis.sk.

The inherited bone marrow failure syndromes (IBMFS) are a group of clinically heterogeneous disorders in which at least one hematopoietic cell lineage is significantly reduced in number.1 Dyskeratosis congenita (DC), an IBMFS caused by germline defects in telomere biology, is diagnosed by the presence of the classic clinical triad of nail dysplasia, lacy skin pigmentation and oral leukoplakia. There are clinical variants of DC, namely Hoyeraal-Hreidarsson syndrome, Revesz syndrome, and Coats plus syndrome (CpS) or cerebroretinal microangiopathy with calcification and cysts.2 CpS is a very rare disorder in which the most characteristic features are: retinal telangiectasia and exudates (Coats disease); distinctive pattern of intracranial calcification with …

Dyskeratosis congenita (DC) is a genetic syndrome with an increasingly appreciated myriad of disease manifestations including life-threatening bone marrow failure (BMF), pulmonary fibrosis, hepatic cirrhosis, and cancer predisposition. Driven by defects in telomere length maintenance, DC is one of a spectrum of telomere biology disorders (TBDs), which includes familial pulmonary fibrosis and the severe variants, Hoyeraal-Hreidarsson syndrome, Revesz syndrome, and Coats plus. To date, genes implicated in the TBDs encode telomerase core components (TERT and TERC), factors required for telomerase biogenesis (DKC1, NHP2, NOP2, NAF1, and PARN), telomerase trafficking (WRAP53), telomerase recruitment (ACD), telomere replication and end structure (RTEL1, CTC1, STN1, and POT1), and multiple aspects of telomere biology (TINF2). In this chapter, the principles of telomere length maintenance are described, and a current appraisal of the diagnosis, disease manifestations, treatment options, and molecular genetics of DC and related TBDs is provided.

Revesz syndrome is a telomere disorder in the dyskeratosis congenita (DKC) spectrum characterized by exudative retinopathy, bone marrow failure, neuroradiographic abnormalities, and integumentary findings.We report the ophthalmologic findings, documented by examinations under anesthesia with clinical photography and fluorescein angiography, as well as the systemic manifestations and genetic and molecular testing, in identical twins with Revesz syndrome, and compare and contrast these features to those of other pediatric retinal vasculopathies.Both twins exhibited widespread avascularity and anomalous vasculature of the retinal periphery, retinal telangiectasias, and exudation. One twin developed a combination exudative/tractional/rhegmatogenous retinal detachment, while the other exhibited a focal collection of buds of retinal neovascularization. Both twins developed bone marrow failure and were found to have cerebellar hypoplasia and widespread cerebral calcifications. Telomere testing in lymphocytes and granulocytes revealed telomere length less than the 1st percentile for age, and gene sequencing revealed a novel mutation in the TINF2 gene, resulting in the T284P TIN2 protein variant.We report ophthalmic findings in twins with Revesz syndrome due to a previously unreported mutation in TINF2 and propose that phenotypic and molecular overlaps between DKC spectrum disorders and pediatric retinal vasculopathies may reflect a shared pathophysiologic basis.

ObjectiveWe systematically evaluated CNS manifestations in patients with inherited telomere biology disorders (TBDs) to better understand the clinical and biological consequences of germline aberrations in telomere biology.MethodsForty-four participants with TBDs (31 dyskeratosis congenita, 12 Hoyeraal-Hreidarsson syndrome, and 1 Revesz syndrome) enrolled in an institutional review board–approved longitudinal cohort study underwent detailed clinical assessments, brain MRI, and genetic testing. Lymphocyte telomere length Z-scores were calculated to adjust for age.ResultsIn this cohort, 25/44 (57%) patients with a TBD had at least 1 structural brain abnormality or variant, most commonly cerebellar hypoplasia (39%). Twenty-one patients (48%) had neurodevelopmental disorder or psychomotor abnormality. Twelve had psychiatric diagnoses, including depression and/or anxiety disorders. Other findings such as hypomyelination, prominent cisterna magna, and cavum septum pellucidum were more frequent than in the general population (p < 0.001). Shorter lymphocyte telomere length was associated with an increased number of MRI findings (p = 0.02) and neurodevelopmental abnormalities (p < 0.001). Patients with autosomal recessive or X-linked TBDs had more neurologic findings than those with autosomal dominant disease.ConclusionsStructural brain abnormalities and variants are common in TBDs, as are neurologic and psychiatric symptoms. The connection between neurodevelopment and telomere biology warrants future study.

Dyskeratosis congenita (DC) is a cancer-prone inherited bone marrow failure syndrome caused by aberrant telomere biology. The mucocutaneous triad of nail dysplasia, abnormal skin pigmentation and oral leukoplakia is diagnostic, but is not always present; DC can also be diagnosed by the presence of very short leukocyte telomeres. Patients with DC are at high risk of bone marrow failure, pulmonary fibrosis, liver disease, cancer and other medical problems. Germline mutations in one of nine genes associated with telomere maintenance are present in approximately 60% of patients. DC is one among the group of clinically and biologically related telomere biology disorders, including Hoyeraal–Hreidarsson syndrome, Revesz syndrome, Coats plus (also known as cranioretinal microangiopathy with calcifications and cysts) and subsets of aplastic anemia, pulmonary fibrosis, nonalcoholic and noninfectious liver disease and leukemia. The authors review the pathobiology that connects DC and the related telomere biology disorders, methods of diagnosis and management modalities.

Dyskeratosis congenita (DC) is the prototypical member of a family of diseases caused by defective telomere maintenance. These “telomeropathies” also include Hoyeraal-Hreidarsson syndrome (HH) and Revesz syndrome, which are severe forms of dyskeratosis congenita, as well as a subset of idiopathic pulmonary fibrosis, aplastic anemia, and Coats' plus syndrome. Retinopathy has only rarely been reported in DC and HH, but is universally present in Coats' plus and Revesz syndromes. The care of these patients is typically a multidisciplinary effort, and this should include monitoring by an ophthalmologist. [ Ophthalmic Surg Lasers Imaging Retina . 2016;47:366–368.]

Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) is a rare multisystem disorder characterized by extensive intracranial calcifications and cysts, leukoencephalopathy, and retinal vascular abnormalities. Additional features include poor growth, skeletal and hematological abnormalities, and recurrent gastrointestinal bleedings. Autosomal-recessive inheritance has been postulated. The pathogenesis of CRMCC is unknown, but its phenotype has key similarities with Revesz syndrome, which is caused by mutations in TINF2, a gene encoding a member of the telomere protecting shelterin complex. After a whole-exome sequencing approach in four unrelated individuals with CRMCC, we observed four recessively inherited compound heterozygous mutations in CTC1, which encodes the CTS telomere maintenance complex component 1. Sanger sequencing revealed seven more compound heterozygous mutations in eight more unrelated affected individuals. Two individuals who displayed late-onset cerebral findings, a normal fundus appearance, and no systemic findings did not have CTC1 mutations, implying that systemic findings are an important indication for CTC1 sequencing. Of the 11 mutations identified, four were missense, one was nonsense, two resulted in in-frame amino acid deletions, and four were short frameshift-creating deletions. All but two affected individuals were compound heterozygous for a missense mutation and a frameshift or nonsense mutation. No individuals with two frameshift or nonsense mutations were identified, which implies that severe disturbance of CTC1 function from both alleles might not be compatible with survival. Our preliminary functional experiments did not show evidence of severely affected telomere integrity in the affected individuals. Therefore, determining the underlying pathomechanisms associated with deficient CTC1 function will require further studies.

Two siblings presenting with exudative retinopathy, thrombocytopenia, and macrocytosis were found to have markedly shortened telomeres and a previously unreported inherited mutation in TERT, c.2603A>G. Revesz syndrome, a subtype of dyskeratosis congenita (DC) caused by TINF2 mutation, combines marrow failure with exudative retinopathy, intracranial calcifications, and neurocognitive impairment. As our patients manifested neither intracranial calcification nor significant neurocognitive impairment, we conclude that the c.2603A>G TERT mutation may define a subtype of DC manifesting first as exudative retinopathy without other signs of DC. Children with exudative retinopathy should be periodically screened for macrocytosis and cytopenias to evaluate for underlying DC.

Purpose The inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of genetic disorders that share the inability of the bone marrow to produce an adequate number of blood cells. The 4 most frequent syndromes are Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS). All 4 syndromes have been associated with various physical abnormalities. As part of a genotype/phenotype/cancer susceptibility study, we determined the prevalence of ophthalmic manifestations in these 4 syndromes. Design Cross-sectional study of a patient cohort. Participants Seventy-five patients with an IBMFS and 121 of their first-degree relatives were seen in the National Eye Institute, National Institutes of Health, from 2001 to 2007. The patient group included 22 with FA, 28 with DC, 19 with DBA, and 6 with SDS. Methods Every participant underwent a complete ophthalmic evaluation and digital facial photography with an adhesive paper ruler on the patient's forehead for an internal measure of scale. Interpupillary distance (IPD), inner canthal distance (ICD), outer canthal distance (OCD), palpebral fissure length (PFL), and corneal diameter (CD) were measured. Thirteen of the 22 patients with FA underwent axial length (AL) measurements by A-scan ultrasonography. Main Outcome Measures Type and prevalence of ophthalmic manifestations. Results Ninety-five percent of patients with FA had at least 1 abnormal parameter, and 25% of patients had at least 4 abnormal parameters. Eighty-two percent of patients had small palpebral fissures, 69% of patients had simple microphthalmia, 64% of patients had small OCD, 55% of patients had microcornea, 28% of patients had ptosis, and 6% of patients had epicanthal folds. In patients with DC, abnormalities of the lacrimal drainage system (29%) were the most prevalent findings, followed by retinal abnormalities (pigmentary changes, retinal neovascularization, retinal detachment, exudative retinopathy) in 21%, cicatricial entropion with trichiasis and blepharitis in 7% each, and sparse eyelashes and congenital cataract in 3.5% each. No significant ophthalmic abnormalities were seen in patients with DBA or SDS. Conclusions Syndrome-specific ocular findings are associated with FA and DC and may antedate diagnosis of the specific syndrome. Early recognition of these abnormalities is important for optimal management. Financial Disclosure(s) The authors have no proprietary or commercial interest in any materials discussed in this article.

Dyskeratosis congenita (DC) is a multisystem bone marrow failure syndrome characterized by a triad of mucocutaneous abnormalities and a predisposition to cancer. The genetic basis of DC remains unknown in more than 60% of patients. Mutations have been identified in components of the telomerase complex (dyskerin, TERC, TERT, NOP10, and NHP2), and recently in one component of the shelterin complex TIN2 (gene TINF2). To establish the role of TINF2 mutations, we screened DNA from 175 uncharacterised patients with DC as well as 244 patients with other bone marrow failure disorders. Heterozygous coding mutations were found in 33 of 175 previously uncharacterized DC index patients and 3 of 244 other patients. A total of 21 of the mutations affected amino acid 282, changing arginine to histidine (n = 14) or cysteine (n = 7). A total of 32 of 33 patients with DC with TINF2 mutations have severe disease, with most developing aplastic anaemia by the age of 10 years. Telomere lengths in patients with TINF2 mutations were the shortest compared with other DC subtypes, but TERC levels were normal. In this large series, TINF2 mutations account for approximately 11% of all DC, but they do not play a significant role in patients with related disorders. This study emphasises the role of defective telomere maintenance on human disease.

We present a child with Fanconi anaemia and congenital hypopituitarism, who developed intracerebral calcifications, progressive spasticity and retinopathy. The chromosome fragility with mitomycin C was increased in both the patient and his sibling, confirming a diagnosis of Fanconi anaemia. Aplastic anaemia in association with intracerebral calcifications has been described in patients with dyskeratosis congenita and Revesz syndrome, but not so far in confirmed cases of Fanconi anaemia. This case further illustrates the greater overlap of associated features in congenital bone marrow failure syndromes. It also indicates that Fanconi anaemia should be actively excluded where such associated features are found.

A 13-month-old boy with mild hemophilia A presented for strabismus evaluation and was found to have retinal hemorrhages in the right eye, left exotropia, and left total retinal detachment. These findings were attributed to trauma and hemophilia A. Routine blood work for hemophilia A subsequently showed pancytopenia. A bone marrow aspirate showed marked hypocellularity consistent with severe aplastic anemia, and telomere testing revealed very short telomeres. The patient was found to have a TINF2 mutation consistent with a diagnosis of Revesz syndrome, a variant of dyskeratosis congenita. He underwent successful bone marrow transplantation, and on subsequent evaluation was found to have retinal hemorrhages, vessel sclerosis, and cotton wool spots in the right eye associated with peripheral retinal nonperfusion. He underwent retinal laser treatment to the areas of retinal nonperfusion which resulted in stable visual function.

Dyskeratosis congenita (DC) is a complex syndrome exhibiting marked clinical and genetic heterogeneity. In its classic form it is characterized by mucocutaneous abnormalities, bone marrow (BM) failure, and a predisposition to cancer. Studies over the past 15 years have led to significant advances with 10 DC genes (DKC1, TERC, TERT, NOP10, NHP2, TINF2, C16orf57/USB1, TCAB1, CTC1, and RTEL1) having been characterized. Nine of these are important in telomere maintenance, and patients usually have very short telomeres. These genetic advances have led to the unification of DC with a number of other disorders. This includes the severe disorders Hoyeraal-Hreidarsson (HH) and Revesz syndromes, which are often characterized by a variable immune deficiency. This wide spectrum of diseases ranging from classic DC to HH can be regarded as disorders of defective telomere maintenance – “the telomereopathies.” These advances have highlighted the important role of telomerase/telomeres in human biology, and are facilitating management of DC.

Abnormal development of the retinal vasculature is an important cause of vision loss in infancy, childhood and, occasionally, in adult life. In addition to retinopathy of prematurity from exposure to oxygen after preterm birth, several genetic defects affecting retinal vascularization have recently been discovered, affecting either Wnt signaling or telomere maintenance. The canonical norrin–beta-catenin pathway of Wnt signaling is deranged by mutations in frizzeld-4 (FZD4), low density lipoprotein receptor-related protein 5 (LRP5), norrin (NDP) and other genes. These lead to vascular leakage, vitreoretinal traction or both in Coats’ disease, familial exudative vitreoretinopathy (FEVR), Norrie’s disease and osteoporosis-pseudoglioma syndrome. Mutations in telomeric repeat-binding factor 1-interacting nuclear factor 2 (TINF2) and CTS telomere maintenance complex component 1 (CTC1) in Revesz syndrome and cerebroretinal microangiopathy with calcifications and cysts (CRMCC) can even cause retinal angiomas. Wnt signaling initially was the suspect for them as well, because all six diseases share more or less widespread retinal avascularity as a hallmark. Indeed, a link between the two pathways is still possible. The manifestations of the telomere-related syndromes are more protean than those of Wnt-related ones, which have no other significant systemic findings than osteoporosis if LRP5 is mutated. The former may lead to a cerebral and intestinal vasculopathy or hepatopathy, all of which can be fatal, and to skin and hair abnormalities. Milder forms can escape diagnosis until adulthood. It is useful to recognize these genetic vasculopathies. Genes for cases which still go unexplained remain to be discovered.

Mutations in CTC1, which encodes a key telomere component, have been identified as the cause of Coats plus syndrome. This discovery provides an important pathophysiological link between Coats plus and the clinically related telomere disorders dyskeratosis congenita, Revesz syndrome and Hoyeraal-Hreidarsson syndrome.

A 2-year-old girl presented with thrombocytopenic purpura. Clinical examination and follow-up documented severe bone marrow hypoplasia associated with bilateral progressive Coasts retinopathy, nail dystrophy, fine hair, and apparent chromosome instability. The syndrome is regarded as a variant of the Revesz syndrome sharing some findings of dyskeratosis congenita. © 1994 Wiley-Liss, Inc.

Dyskeratosis congenita (DC) is a telomere biology disorder characterized by a mucocutaneous triad, aplastic anemia, and predisposition to cancer. Mutations in a narrow segment of TINF2 exon 6 have been recognized to cause often-severe DC that is either sporadic or autosomal dominant. We describe three children with very early presentations of DC, including one with the severe variant known as Revesz syndrome. Although most TINF2 mutations reported to date are missense changes, each of our patients carried a novel heterozygous nonsense or frameshift mutation, revealing a new 5' boundary to the affected gene segment in patients with DC. Examination of patient-derived lymphoblastoid cell lines revealed stable expression of the predicted truncated TIN2 proteins. In co-immunoprecipitation assays, the ability of a truncation mutant to interact with TRF1 was severely impaired, whereas the ability of the most common DC-associated mutant was much less affected. This suggests that the disruption of TIN2-TRF1 interaction may contribute to the severe clinical phenotype observed in the context of the TIN2 truncation mutation, but is unlikely to be the primary cause of telomere shortening associated with the more prevalent TIN2 missense mutations. Telomere flow-fluorescent in situ hybridization (FISH) analysis of one pedigree showed the dramatic effect a de novo nonsense TINF2 mutation had on telomere length in early development. These cases underscore the severe manifestations of truncating TINF2 mutations.

Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by the triad of abnormal nails, lacey reticular skin pigmentation, and oral leukoplakia. Patients with DC are at high risk of developing aplastic anemia, myelodysplastic syndrome and leukemia. Diagnosis of DC is challenging due to variability of the triad and heterogeneous clinical findings such as pulmonary and liver disease, avascular necrosis, esophageal or urethral stenosis and development delay. The unifying feature in DC is exceedingly short telomere lengths and defects in telomere biology. Gene mutations have been identified in DKC1 (X-linked), TERC and TERT (dominant, AD) and NOP10 (recessive), but approximately 60% of DC patients lack a known mutation. We identified a non-consanguineous family with AD DC and no mutations in DKCI, TERC or TERT. The first DC cases were monozygotic twin brothers (now deceased). Telomere length was determined by flow-FISH on the twins’ children (6 affected, 4 unaffected), wives, their 8 siblings and parents. Despite variable clinical phenotypes, the 6 affected individuals (1 female, 5 male) all had very short telomere lengths (

Revesz syndrome is a variant of dyskeratosis congenita characterized by aplastic anemia, retinopathy, and central nervous system abnormalities. We describe a 3-year-old boy in whom the spectrum of neuroimaging findings, including intracranial calcifications, cerebellar hypoplasia and unusual brain lesions were found by biopsy to be gliosis despite their enhancement and progression. In patients with dyskeratosis-related syndromes, non-neoplastic parenchymal brain lesions occur and gliosis should be considered in the differential diagnosis for progressive enhancing brain lesions. Should this finding be confirmed consistently in additional cases, brain biopsy could potentially be avoided.

We report a case of a 12-year-old boy with history of myelofibrosis and retinopathy who developed sudden neurological deficits associated with coagulopathy, multiorgan failure, and death. A fluorescent in situ hybridization study revealed monosomy of chromosome 7 in 21% of the bone marrow cells in support of his diagnosis of myelofibrosis. Postmortem neuropathology examination revealed multiple coarse and microcalcifications and cerebral hemorrhages, explaining the patient's neurological deterioration. The findings of myelofibrosis, retinopathy, and cerebral calcifications indicate that this could be a case of a rare condition known as Revesz syndrome.

Response to the article by Linnankivi et al. , entitled ‘Cerebroretinal microangiopathy with calcifications and cyst, Revesz syndrome and aplastic anemia’

A male infant was found to have bilateral exudative retinopathy at 6 months of age. A month later severe aplastic anaemia was diagnosed, eventually leading to the infant's death. Additional features of this seemingly new syndrome were intrauterine growth retardation, fine sparse hair, fine reticulate skin pigmentation, ataxia because of cerebellar hypoplasia, cerebral calcifications, extensor hypertonia, and progressive psychomotor retardation.

This study was designed to evaluate the utility of flow-FISH telomere length measurement in white blood cells (WBC) as a screening test for Dyskeratosis congenita (DC). We studied 26 patients: 17 with DC, 1 silent carrier (clinically normal; mutation in TERC), 4 with the Hoyeraal-Hreidarsson variant (HH), and 4 with Revesz Syndrome. Five had mutations in DKC1, 5 in TERC, and 2 in TERT. 23 had hematologic abnormalities, 19 had 2 or 3 of the DC diagnostic triad (lacey pigmentation, dyskeratotic nails, and leukoplakia), and 4 had soft signs of DC. We evaluated 54 first-degree relatives of DC patients, 16 Fanconi Anemia patients (FA), 14 with Diamond-Blackfan Anemia (DBA), 5 with Shwachman Diamond Syndrome (SDS), and 10 with other possibly inherited cytopenias (Other). Telomere length was measured in granulocytes and lymphocyte subsets by automated multicolor flow-FISH; results were compared with age-matched values from 400 normal controls. “Very low (VL)” telomere length was defined as a mean telomere length below the normal first percentile for age and specific WBC type. We observed VL telomeres in all subsets in the silent carrier, all HH and Revesz patients, and 15/17 with DC. Eight of 51 DC relatives had VL telomeres in granulocytes versus 2/54 with VL telomeres in lymphocytes. The sensitivities for distinguishing a DC patient from an unaffected relative were 92% in lymphocytes and 96% in granulocytes; the specificities were 96% and 98%, respectively; the sensitivity and specificity for VL telomeres in both cell types were 96% and 96%. The silent carrier with a TERC mutation developed thrombocytopenia, hypocellular marrow, and a cytogenetic clone during follow-up. The 2 DC relatives with VL telomeres in lymphocytes were from a family without a known mutant gene; they may also be silent carriers. The latter possibility disqualified an HLA-matched sibling as a donor for DC-related aplastic anemia, because of engraftment concerns; another sibling donor with normal telomere length was selected. VL granulocyte telomeres were observed in 5/16 FA, 3/14 DBA, 1/5 SDS, and 1/10 Other patients, versus 2/16 FA, 1/14 DBA, 1/5 SDS, and 0/10 Other in lymphocytes, and in both lineages in only 1 each of FA, DBA, and SDS. The sensitivity and specificity for distinguishing DC from non-DC patients using VL telomeres in both lineages were 96% and 93%, respectively. Only DC patients had consistently VL telomeres in all cell subsets. Flow-FISH telomere length measurement provides a sensitive and specific method for identifying patients with DC among families, regardless of mutation status, and distinguishes patients with DC from those with other inherited or acquired marrow failure syndromes. It may also help to detect silent carriers, and facilitate identification of mutations in other telomere biology genes. Our data suggest that the diagnostic triad, soft physical findings and/or bone marrow failure may not be required for the diagnosis of DC. Correct diagnosis of DC will enhance genetic counseling and hematologic management.