Features of clinic cohort participants at the NIH Clinical Center evaluation
| Number of patients . | Total, n (%) . | AD, n (%) . | AR/XLR, n (%) . | TINF2, n (%) . | Unknown, n (%) . |
|---|---|---|---|---|---|
| 91 . | 42 . | 28 . | 14 . | 7 . | |
| Age at NIH visit, median [range] | 23.8 [1.4-69.4] | 38.4 [1.5-69.4] | 14.5 [1.4-46.3] | 13.1 [2.1-31.4] | 13.1 [7.4-30.2] |
| Median follow-up in years since NIH visit [range] | 7.1 [0-17.1] | 7.1 [0-17.1] | 6.4 [0-14.5] | 12.6 [1.4-15.6] | 5.8 [0-8.5] |
| Consanguinity | 2 (2.2) | 0 | 2 (7.1) | 0 | 0 |
| Prematurity* | 20 (22) | 6 (14.3) | 8 (28.6) | 3 (21.4) | 3 (42.9) |
| Small for gestational age† [records available] | 26 [81] (32.1) | 4 [32] (12.5) | 16 [28] (57.1) | 3 [14] (21.4) | 3 [7] (42.9) |
| Short stature‡ | 6 (6.6) | 2 (4.8) | 3 (10.7) | 0 | 1 (14.3) |
| Number of triad features§ | |||||
| 0 | 38 (41.8) | 31 (73.8) | 5 (17.8) | 2 (14.2) | 0 |
| 1 | 14 (15.4) | 7 (16.7) | 3 (10.7) | 2 (14.2) | 2 (28.6) |
| 2 | 12 (13.2) | 1 (2.4) | 7 (25) | 1 (7.1) | 3 (42.9) |
| 3 | 27 (29.7) | 3 (7.1) | 13 (46.4) | 9 (64.3) | 2 (28.6) |
| BMFǁ | |||||
| None | 35 (38.5) | 26 (61.9) | 5 (17.9) | 1 (7.1) | 3 (42.9) |
| Nonsevere | 23 (25.3) | 9 (21.4) | 8 (28.6) | 4 (28.6) | 2 (28.6) |
| Severe | 33 (36.3) | 7 (16.7) | 15 (53.6) | 9 (64.3) | 2 (28.6) |
| Immunologic abnormality¶ [available records] | 30 [84] (35.7)# | 11 [40] (27.5) | 13 [27] (48.1) | 4 [11] (36.4) | 2 [6] (33.3) |
| Lymphocyte subset reduced** [available records] | 27 [77] (35.1) | 10 [39] (25.6) | 12 [23] (52.2) | 3 [9] (33.3) | 2 [6] (33.3) |
| Low IgM/IgG [available records] | 8 [82] (9.8) | 1 [38] (2.6) | 5 [27] (18.5) | 1 [11] (9.1) | 1 [6] (16.7) |
| Neurological | |||||
| Microcephaly [available records]†† | 17 [82] (20.7) | 2 [34] (5.9) | 10 [28] (35.7) | 3 [14] (21.4) | 2 [6] (33.3) |
| Cerebellar hypoplasia‡‡ [available imaging records] | 22 [59] (37.3) | 3 [17] (17.6) | 15 [25] (60) | 2 [10] (20) | 2 [7] (28.6) |
| Developmental delay | 26 (28.6) | 2 (4.8) | 20 (71.4) | 4 (28.6) | 0 |
| Ataxia | 14 (15.4) | 2 (4.8) | 9 (32.1) | 3 (21.4) | 0 |
| Ophthalmologic abnormalitiesa | 29 (31.9) | 4 (9.5) | 12 (42.9) | 10 (71.4) | 3 (42.9) |
| Epithelial: lacrimal duct stenosis, epiphora, blepharitis, trichiasis | 25 (27.5) | 3 (7.1) | 11 (39.3) | 9 (64.3) | 2 (28.6) |
| Retinal: retinopathy, retinal hemorrhage, retinal neovascularization/vascular sheathing [available records] | 7b [82] (8.5) | 1 [36] (2.8) | 2 [25] (8) | 3b [14] (21.4) | 1 [7] (14.3) |
| Taurodontism [total of dental consults] | 21 [70] (30) | 7 [31] (22.6) | 9 [23] (39.1) | 2 [11] (18.2) | 3 [5] (60) |
| Hearing loss [available records] | 4 [90] (4.4) | 1 [42] (2.4) | 1 [27] (3.7) | 1 [14] (7.1) | 1 [7] (14.3) |
| Congenital cardiac disease | 2 (2.2)c | 0 | 1 (3.6) | 0 | 1 (14.3) |
| Pulmonary fibrosis | 6 (6.6) | 5 (11.9) | 0 | 0 | 1 (14.3) |
| Prior to HCT | 6 (6.6) | 5 (11.9) | 0 | 0 | 1 (14.3) |
| Following HCT | 0 | 0 | 0 | 0 | 0 |
| Pulmonary arteriovenous malformations | 0 | 0 | 0 | 0 | 0 |
| Liver disease | 3 (3.3) | 0 | 2 (7.1) | 0 | 1 (14.3) |
| Portal hypertension | 2 (2.2) | 0 | 2 (7.1) | 0 | 0 |
| Liver fibrosis/cirrhosis | 1 (1.1) | 0 | 0 | 0 | 1 (14.3) |
| Gastrointestinal | |||||
| Esophageal strictures | 7 (7.7) | 0 | 7 (25) | 0 | 0 |
| Failure to thrive | 8 (8.8) | 0 | 6 (21.4) | 1 (7.1) | 1 (14.3) |
| Telangiectasiad | 1 (1.1) | 0 | 1 (3.6) | 0 | 0 |
| Genitourinary system | |||||
| Kidney structural abnormalitiese | 3 (3.3) | 1 (2.4) | 1 (3.6) | 1 (7.1) | 0 |
| Urethral stricture [number of males] | 6 [57] (10.5) | 0 [18] (0) | 3 [23] (13) | 2 [12] (16.7) | 1 [4] (25) |
| Undescended testis [number of males] | 4 [57] (7) | 2 [18] (11.1) | 2 [23] (8.7) | 0 [12] (0) | 0 [4] (0) |
| Endocrine system | |||||
| Hypothyroidism or diabetes mellitus, type 1 or 2 | 12 (13.2) | 6 (14.3) | 5 (17.9) | 0 (0) | 1 (14.3) |
| Skeletal system | |||||
| Avascular osteonecrosis | 5 (5.5) | 2 (4.8) | 2 (7.1) | 0 (0) | 1 (14.3) |
| Low bone density [number of DEXA scans] | 12 [38] (31.6) | 5 [14] (35.7) | 5 [13] (38.5) | 2 [7] (28.6) | 0 [4] (0) |
| Number of patients . | Total, n (%) . | AD, n (%) . | AR/XLR, n (%) . | TINF2, n (%) . | Unknown, n (%) . |
|---|---|---|---|---|---|
| 91 . | 42 . | 28 . | 14 . | 7 . | |
| Age at NIH visit, median [range] | 23.8 [1.4-69.4] | 38.4 [1.5-69.4] | 14.5 [1.4-46.3] | 13.1 [2.1-31.4] | 13.1 [7.4-30.2] |
| Median follow-up in years since NIH visit [range] | 7.1 [0-17.1] | 7.1 [0-17.1] | 6.4 [0-14.5] | 12.6 [1.4-15.6] | 5.8 [0-8.5] |
| Consanguinity | 2 (2.2) | 0 | 2 (7.1) | 0 | 0 |
| Prematurity* | 20 (22) | 6 (14.3) | 8 (28.6) | 3 (21.4) | 3 (42.9) |
| Small for gestational age† [records available] | 26 [81] (32.1) | 4 [32] (12.5) | 16 [28] (57.1) | 3 [14] (21.4) | 3 [7] (42.9) |
| Short stature‡ | 6 (6.6) | 2 (4.8) | 3 (10.7) | 0 | 1 (14.3) |
| Number of triad features§ | |||||
| 0 | 38 (41.8) | 31 (73.8) | 5 (17.8) | 2 (14.2) | 0 |
| 1 | 14 (15.4) | 7 (16.7) | 3 (10.7) | 2 (14.2) | 2 (28.6) |
| 2 | 12 (13.2) | 1 (2.4) | 7 (25) | 1 (7.1) | 3 (42.9) |
| 3 | 27 (29.7) | 3 (7.1) | 13 (46.4) | 9 (64.3) | 2 (28.6) |
| BMFǁ | |||||
| None | 35 (38.5) | 26 (61.9) | 5 (17.9) | 1 (7.1) | 3 (42.9) |
| Nonsevere | 23 (25.3) | 9 (21.4) | 8 (28.6) | 4 (28.6) | 2 (28.6) |
| Severe | 33 (36.3) | 7 (16.7) | 15 (53.6) | 9 (64.3) | 2 (28.6) |
| Immunologic abnormality¶ [available records] | 30 [84] (35.7)# | 11 [40] (27.5) | 13 [27] (48.1) | 4 [11] (36.4) | 2 [6] (33.3) |
| Lymphocyte subset reduced** [available records] | 27 [77] (35.1) | 10 [39] (25.6) | 12 [23] (52.2) | 3 [9] (33.3) | 2 [6] (33.3) |
| Low IgM/IgG [available records] | 8 [82] (9.8) | 1 [38] (2.6) | 5 [27] (18.5) | 1 [11] (9.1) | 1 [6] (16.7) |
| Neurological | |||||
| Microcephaly [available records]†† | 17 [82] (20.7) | 2 [34] (5.9) | 10 [28] (35.7) | 3 [14] (21.4) | 2 [6] (33.3) |
| Cerebellar hypoplasia‡‡ [available imaging records] | 22 [59] (37.3) | 3 [17] (17.6) | 15 [25] (60) | 2 [10] (20) | 2 [7] (28.6) |
| Developmental delay | 26 (28.6) | 2 (4.8) | 20 (71.4) | 4 (28.6) | 0 |
| Ataxia | 14 (15.4) | 2 (4.8) | 9 (32.1) | 3 (21.4) | 0 |
| Ophthalmologic abnormalitiesa | 29 (31.9) | 4 (9.5) | 12 (42.9) | 10 (71.4) | 3 (42.9) |
| Epithelial: lacrimal duct stenosis, epiphora, blepharitis, trichiasis | 25 (27.5) | 3 (7.1) | 11 (39.3) | 9 (64.3) | 2 (28.6) |
| Retinal: retinopathy, retinal hemorrhage, retinal neovascularization/vascular sheathing [available records] | 7b [82] (8.5) | 1 [36] (2.8) | 2 [25] (8) | 3b [14] (21.4) | 1 [7] (14.3) |
| Taurodontism [total of dental consults] | 21 [70] (30) | 7 [31] (22.6) | 9 [23] (39.1) | 2 [11] (18.2) | 3 [5] (60) |
| Hearing loss [available records] | 4 [90] (4.4) | 1 [42] (2.4) | 1 [27] (3.7) | 1 [14] (7.1) | 1 [7] (14.3) |
| Congenital cardiac disease | 2 (2.2)c | 0 | 1 (3.6) | 0 | 1 (14.3) |
| Pulmonary fibrosis | 6 (6.6) | 5 (11.9) | 0 | 0 | 1 (14.3) |
| Prior to HCT | 6 (6.6) | 5 (11.9) | 0 | 0 | 1 (14.3) |
| Following HCT | 0 | 0 | 0 | 0 | 0 |
| Pulmonary arteriovenous malformations | 0 | 0 | 0 | 0 | 0 |
| Liver disease | 3 (3.3) | 0 | 2 (7.1) | 0 | 1 (14.3) |
| Portal hypertension | 2 (2.2) | 0 | 2 (7.1) | 0 | 0 |
| Liver fibrosis/cirrhosis | 1 (1.1) | 0 | 0 | 0 | 1 (14.3) |
| Gastrointestinal | |||||
| Esophageal strictures | 7 (7.7) | 0 | 7 (25) | 0 | 0 |
| Failure to thrive | 8 (8.8) | 0 | 6 (21.4) | 1 (7.1) | 1 (14.3) |
| Telangiectasiad | 1 (1.1) | 0 | 1 (3.6) | 0 | 0 |
| Genitourinary system | |||||
| Kidney structural abnormalitiese | 3 (3.3) | 1 (2.4) | 1 (3.6) | 1 (7.1) | 0 |
| Urethral stricture [number of males] | 6 [57] (10.5) | 0 [18] (0) | 3 [23] (13) | 2 [12] (16.7) | 1 [4] (25) |
| Undescended testis [number of males] | 4 [57] (7) | 2 [18] (11.1) | 2 [23] (8.7) | 0 [12] (0) | 0 [4] (0) |
| Endocrine system | |||||
| Hypothyroidism or diabetes mellitus, type 1 or 2 | 12 (13.2) | 6 (14.3) | 5 (17.9) | 0 (0) | 1 (14.3) |
| Skeletal system | |||||
| Avascular osteonecrosis | 5 (5.5) | 2 (4.8) | 2 (7.1) | 0 (0) | 1 (14.3) |
| Low bone density [number of DEXA scans] | 12 [38] (31.6) | 5 [14] (35.7) | 5 [13] (38.5) | 2 [7] (28.6) | 0 [4] (0) |
AD, autosomal dominant; AR, autosomal recessive; BMF, bone marrow failure; DEXA, dual energy X-ray absorptiometry; GI, gastrointestinal; HCT, hematopoietic cell transplantation; NIH, National Institutes of Health; XLR, X-linked recessive.
Prematurity: <37 gestational weeks.
Definition for small for gestational age: <37 gestational weeks: birthweight <tenth percentile (www.cdc.gov); ≥37 gestational weeks: <2500g.
Definition short stature: height <third percentile for age.
Triad features: mucocutaneous features associated with dyskeratosis congenita. Includes nail dysplasia, lacy/reticular skin pigmentation, leukoplakia.
n = 5 received HCT prior to study. Definition BMF severity: non-severe: absolute neutrophile count (ANC) 500-<1500/mm3, platelets 20 000-<150.000/mm3, and/or Hb ≥8g/dL to less than normal for age. Severe: transfusion dependency, and/or androgen treatment, and/or blood count: ANC <500/mm3, platelets <20 000/mm3, and/or Hb <8.0 g/dL. BMF was always considered severe if HCT had been performed, and/or MDS or leukemia had been diagnosed.
Immunologic diagnostics included lymphocyte subsets and/or immunoglobulin M (IgM) and G (IgG) levels. Immunologic abnormality refers to reduced levels in lymphocyte subsets and/or IgG and/or IgM levels according to the reference levels by the National Institutes of Health laboratory at time of study. Five patients with prior HCT and 1 with current chemotherapy (azacytidine) were excluded from the evaluation. Of the remaining, 84 participants had lymphocyte subsets and/or immunoglobulins done.
Of 30 patients with immunologic abnormalities, 15 had severe BMF and 1 received prednisone at time of study.
Reduced NK cell count n = 22, reduced CD19 B-cell count n = 14, reduced CD3 T-cell count n = 11, reduced CD4 T-cell count n = 12, reduced CD8 T-cell count n = 7.
Head circumference <5th percentile for age.
One patient was reported to have cerebellar hypoplasia on autopsy but was not diagnosed by brain imaging at time of study.
Nine patients were diagnosed with cataracts prior to time of study, which were age related in 5, congenital in 2 (siblings), coexistent to Coats retinopathy in 1, and in the context of Revesz syndrome in 1 case.
One patient had a history of HCT at time of ophthalmologic exam.
One patient with dilated cardiomyopathy and one patient with atrioventricular canal defect.
Esophageal varices diagnosed in the context of portal hypertension.
Structural abnormalities detected were: horseshoe kidney, bilateral renal cysts, duplication of renal collecting system and ureters.