Inherited bone marrow failure syndromes (IBMFS) comprise a group of heterogeneous genetic disorders characterized by single or multilineage cytopenias, distinctive clinical features, and an increased risk of specific malignancies, with considerable overlap in hematologic and physical manifestations. Our objective was to identify specific distinguishing features for each of the major IBMFS by identical systematic evaluations, in the first comparison of all 4 disorders in a single center. Participants were: 23 with Fanconi anemia (FA), 32 with dyskeratosis congenita (DC), 23 with Diamond-Blackfan anemia (DBA) and 7 with Shwachman-Diamond syndrome (SDS). Evaluations included physical characteristics, hematologic data, and abnormalities of the skeletal, ophthalmic, otologic, renal, cardiac, central nervous system (CNS) and endocrine systems. We found a similar frequency of cytopenias (~80%) in all disorders; predominantly multilineage in FA and DC, anemia in DBA, and neutropenia in SDS. 50% of FA patients had clonal marrow cytogenetic abnormalities, of whom 24% had morphologic myelodysplastic syndrome (MDS); 25% of DC patients had clones of whom one had MDS; none with DBA had a clone or MDS; and 4/7 with SDS had clones [i(7)q in one, del(20)q in two, i(X)p in one] but no MDS. Skeletal malformations were frequent in patients with FA (68%). Anomalies unique to FA were radial ray defects (thumb or thumb and radius) in 45%, Klippel-Feil Syndrome in 45%, and fused or partial ribs in 25%. No specific defects were seen in patients with DC or DBA. 3/7 patients with SDS had metaphyseal dysplasia. 80% of FA patients had smaller than normal eye measurements, including one or more of outer canthal distance, inner canthal distance, palpebral fissure length or interpupillary distance, compared with age and sex-matched published controls, unaffected family members and patients with other IBMFS; 75% had small eyes by A-scan and 60% had microcorneas. ~15% of patients with DC, DBA and SDS had small palpebral fissure lengths but no microcorneas. Eye findings unique to DC were lacrimal duct stenosis in 27%, exudative retinopathy in one and proliferative retinopathy with retinal neovascularization in two. Hearing was decreased only in FA, in 65%, associated with abnormalities of tympanic membrane bony island and/or short malleus, with conductive hearing loss in 40%. 40% of FA patients had renal anomalies vs. 3% with DC, 8% with DBA and none with SDS. Congenital cardiac defects were more frequent in patients with DBA (40%) than in those with FA (15%), DC (3%) or SDS (none). 50% of patients with FA, 25% with DBA and 5/7 patients with SDS had short stature (height Z-score <2SD) and microcephaly, whereas in DC only 3% had short stature, and 38% had microcephaly without short stature. Only patients with FA and DC had abnormal brain MRIs: 27% of FA patients had absent corpus callosum and/or septum pellucidum, and 57% had a small pituitary; 38% of DC patients had cerebellar hypoplasia and associated microcephaly, developmental/speech delay and ataxia. 56% of DC patients had at least two features of the diagnostic triad (nail dystrophy, oral leukoplakia, and lacey skin pigmentation). Endocrine abnormalities which were common in FA [hypothyroidism (35%), growth hormone deficiency (25%) and hypogonadism (>90% adults)] were rare in the other IBMFS. However, 90% of the patients with FA, 27% with DC, and 60% with DBA and SDS had reduced bone mineral density on Dexa scan. In this first direct, single center comparison of the 4 major IBMFS, we identified: skeletal anomalies, small eyes, abnormal hearing and endocrine deficiencies in FA; high rates of cardiac defects in DBA; CNS anomalies in FA and DC; microcephaly in all disorders; and reduced bone mineral density in all 4 disorders but highest in FA. Thus, comprehensive systematic investigations detected unique syndrome-specific abnormalities in much higher frequencies than expected based on literature reports. These findings have important clinical consequences and warrant early intervention.

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