Patients with mutations in DNAJC21 meet clinical criteria for SDS
| . | Patient 1 . | Patient 2 (sibling of Patient 3) . | Patient 3 (sibling of Patient 2) . | Patient 4 . |
|---|---|---|---|---|
| Age at presentation | 2.5 y | After birth | After birth | After birth |
| Age at diagnosis with SDS | 2 y 11 mo | <1 y | 7 mo | 2 y 2 mo |
| Age at last follow-up or death | 14 y | 1.5 y | 7 y 4 mo | 11 y |
| Evidence of bone marrow failure (age at testing) | Moderately low blood counts (from 2.5 y) | Severe bone marrow failure on chronic transfusion since birth, was planned for transplantation | Severe pancytopenia (7 y), underwent bone marrow transplantation | Severe pancytopenia (2 y), underwent bone marrow transplantation |
| Neutrophils (>1.5 × 109/L) | 1.08 (3 y), 3.54 (14 y) | Severely low | 1.3 (8 mo), 0.5 (7 y) | 0.4 (2 y) |
| Hemoglobin (>120 g/L) | 67 (3 y), 118 (14 y) | Severely low | 97 (8 mo), 55 (7 y) | 74 (2 y) |
| Platelets (>150 × 109/L) | 22 (3 y), 118 (14 y) | Severely low | 185 (8 mo), 17 (7 y) | 17 (2 y 2 mo) |
| Lymphocytes (>1.5 × 109/L) | 2.56 (3 y), 2.28 (14 y) | UK | 5.83 (8 mo), 1.82 (7 y) | 3.4 (2 y) |
| Reticulocytes (>40 × 10°/L) | 96 (14 y) | UK | 102 (8 mo), 33 (7 y) | 32.5 (2 y 2 mo) |
| MCV (0.5-3 y: 70-86 fL, 7-14 y: 75-96) | 89 (3 y), 94 (14 y) | UK | 77 (8 mo), 83 (7 y) | 87 (2 y) |
| HgF (%) (after 1 y <1.2%) | 29 (2.5 y) | UK | 33 | 11.7 (2 y 2 mo) |
| Bone marrow cellularity* (%) | 40-50 (2.5 y) | Markedly reduced | Mildly reduced (8 mo), 10-50% (7 y) | 10 (2 y 5 mo) |
| Prominent marrow dysplasia | No | No | No | No |
| Marrow cytogenetics | N | N | 46,XY, der(15)t(1;15)(q12;p11) (8 mo-7 y) | N |
| Evidence of pancreatic dysfunction | ||||
| Chronic diarrhea | No | No | No | No, fecal fat in microscopy |
| Lipase (23-300 μ/L) | 22 (2 y 11 mo) | UK | 15 (8 mo) | <25 (2 y 2 mo) |
| Amylase (20-110 μ/L) | 36 (2 y 11mo) | UK | 37 (8 mo) | <30 (2 y 3 mo) |
| Pancreatic isoamylase (≥17 μ/L)† | 10 (2 y 11 mo) | UK | 2 (8 mo) | NA |
| Trypsinogen (>16.6 µg/L) | 12.7 (2 y 11 mo) | 11.9 (12 mo), 9.2 (13 mo) | 20 (8 mo) | 3.4 (2 y 2 mo) |
| Vitamin A levels (0.7-2.1 mmol/L) | 1.0 (2 y 11 mo) | UK | 1.4 (8 mo) | 1.4 (2 y 2 mo) |
| Vitamin D levels 70-250 nmol/L) | 60 (2 y 11 mo) | UK | 39 (8 mo) | 69 (5 y 10 mo) |
| Vitamin E levels (12-46 µmol/L) | 9.3 (2 y 11 mo) | UK | 5.2 (3 y) | 8.4 (2 y 2 mo) |
| INR (0.9-1.1) | 0.9 (2 y 11 mo) | UK | 0.97 (8 mo) | NA |
| Hyperechogenic pancreas on US | Markedly echogenic | UK | Markedly echogenic | Diffusely echogenic |
| Hypodense pancreas on CT | Hypodense pancreas | UK | Hypodense pancreas | NA |
| Patient was diagnosed with pancreatic insufficiency before death. On autopsy (18 mo) he was found to have atrophy of exocrine pancreas with fatty infiltration (no changes in the endocrine pancreas) | Autopsy (7 y 4 mo): pancreatic acinar atrophy | |||
| Metaphyseal dysplasia | Yes | Anomaly of the wrist bone (no further details) | Yes (distal radius and ulna, distal femur, proximal tibia) | No, but have osteopenia and focal metaphyseal irregularity in right proximal femur |
| Cognitive impairment | Yes | UK | Yes | Delayed gross motor development |
| Stature | <3% | 30% (11 mo) | <5% (7.5 mo) | <3% |
| Liver | No hepatomegaly, no elevated liver enzymes | Mild fatty changes of the liver (on autopsy) | No hepatomegaly/mild elevation of liver enzymes in infancy | No hepatomegaly, mild elevation of the liver enzymes |
| Other medical problems | Retinitis pigmentosa, generalized seizures (6 mo, 10 mo), severe eczema, asthma, recurrent otitis media, subtle minor physical malformation (low anterior hairline, deep-set eyes, mildly cupped ears, down-turned corners of the mouth, a horizontal crease on the chin, broad neck and redundant skin, increased creases in the palms and deep folds bilaterally, no hearing deficits | Died at the age of 18 mo due to Staphylococcus aureus sepsis | Retinal dystrophy without pigmentation, low visual acuity, decrease visual field, persistent eczema, failure to thrive, kyphosis, mild high-foot inversion, abnormal dentition, hypopigmentation macule at right thigh (developed after transplant) | |
| Other tests with normal results | Chromosomal breakage studies, telomere length, next-generation sequencing of a panel of known 72 IBMFS genes, targeted sequencing of SBDS, urine organic acid and plasma amino acids, 4X180K oligonucleotide array (Agilent Tech), Affymetrix 6.0 Array | Chromosomal breakage studies, targeted sequencing of SBDS, RMRP, Affymetrix 6.0 Array | Chromosomal breakage studies | |
| Targeted sequencing of SBDS, RMRP, Affymetrix 6.0 Array | ||||
| Mitochondrial DNA deletion analysis (for Pearson syndrome) |
| . | Patient 1 . | Patient 2 (sibling of Patient 3) . | Patient 3 (sibling of Patient 2) . | Patient 4 . |
|---|---|---|---|---|
| Age at presentation | 2.5 y | After birth | After birth | After birth |
| Age at diagnosis with SDS | 2 y 11 mo | <1 y | 7 mo | 2 y 2 mo |
| Age at last follow-up or death | 14 y | 1.5 y | 7 y 4 mo | 11 y |
| Evidence of bone marrow failure (age at testing) | Moderately low blood counts (from 2.5 y) | Severe bone marrow failure on chronic transfusion since birth, was planned for transplantation | Severe pancytopenia (7 y), underwent bone marrow transplantation | Severe pancytopenia (2 y), underwent bone marrow transplantation |
| Neutrophils (>1.5 × 109/L) | 1.08 (3 y), 3.54 (14 y) | Severely low | 1.3 (8 mo), 0.5 (7 y) | 0.4 (2 y) |
| Hemoglobin (>120 g/L) | 67 (3 y), 118 (14 y) | Severely low | 97 (8 mo), 55 (7 y) | 74 (2 y) |
| Platelets (>150 × 109/L) | 22 (3 y), 118 (14 y) | Severely low | 185 (8 mo), 17 (7 y) | 17 (2 y 2 mo) |
| Lymphocytes (>1.5 × 109/L) | 2.56 (3 y), 2.28 (14 y) | UK | 5.83 (8 mo), 1.82 (7 y) | 3.4 (2 y) |
| Reticulocytes (>40 × 10°/L) | 96 (14 y) | UK | 102 (8 mo), 33 (7 y) | 32.5 (2 y 2 mo) |
| MCV (0.5-3 y: 70-86 fL, 7-14 y: 75-96) | 89 (3 y), 94 (14 y) | UK | 77 (8 mo), 83 (7 y) | 87 (2 y) |
| HgF (%) (after 1 y <1.2%) | 29 (2.5 y) | UK | 33 | 11.7 (2 y 2 mo) |
| Bone marrow cellularity* (%) | 40-50 (2.5 y) | Markedly reduced | Mildly reduced (8 mo), 10-50% (7 y) | 10 (2 y 5 mo) |
| Prominent marrow dysplasia | No | No | No | No |
| Marrow cytogenetics | N | N | 46,XY, der(15)t(1;15)(q12;p11) (8 mo-7 y) | N |
| Evidence of pancreatic dysfunction | ||||
| Chronic diarrhea | No | No | No | No, fecal fat in microscopy |
| Lipase (23-300 μ/L) | 22 (2 y 11 mo) | UK | 15 (8 mo) | <25 (2 y 2 mo) |
| Amylase (20-110 μ/L) | 36 (2 y 11mo) | UK | 37 (8 mo) | <30 (2 y 3 mo) |
| Pancreatic isoamylase (≥17 μ/L)† | 10 (2 y 11 mo) | UK | 2 (8 mo) | NA |
| Trypsinogen (>16.6 µg/L) | 12.7 (2 y 11 mo) | 11.9 (12 mo), 9.2 (13 mo) | 20 (8 mo) | 3.4 (2 y 2 mo) |
| Vitamin A levels (0.7-2.1 mmol/L) | 1.0 (2 y 11 mo) | UK | 1.4 (8 mo) | 1.4 (2 y 2 mo) |
| Vitamin D levels 70-250 nmol/L) | 60 (2 y 11 mo) | UK | 39 (8 mo) | 69 (5 y 10 mo) |
| Vitamin E levels (12-46 µmol/L) | 9.3 (2 y 11 mo) | UK | 5.2 (3 y) | 8.4 (2 y 2 mo) |
| INR (0.9-1.1) | 0.9 (2 y 11 mo) | UK | 0.97 (8 mo) | NA |
| Hyperechogenic pancreas on US | Markedly echogenic | UK | Markedly echogenic | Diffusely echogenic |
| Hypodense pancreas on CT | Hypodense pancreas | UK | Hypodense pancreas | NA |
| Patient was diagnosed with pancreatic insufficiency before death. On autopsy (18 mo) he was found to have atrophy of exocrine pancreas with fatty infiltration (no changes in the endocrine pancreas) | Autopsy (7 y 4 mo): pancreatic acinar atrophy | |||
| Metaphyseal dysplasia | Yes | Anomaly of the wrist bone (no further details) | Yes (distal radius and ulna, distal femur, proximal tibia) | No, but have osteopenia and focal metaphyseal irregularity in right proximal femur |
| Cognitive impairment | Yes | UK | Yes | Delayed gross motor development |
| Stature | <3% | 30% (11 mo) | <5% (7.5 mo) | <3% |
| Liver | No hepatomegaly, no elevated liver enzymes | Mild fatty changes of the liver (on autopsy) | No hepatomegaly/mild elevation of liver enzymes in infancy | No hepatomegaly, mild elevation of the liver enzymes |
| Other medical problems | Retinitis pigmentosa, generalized seizures (6 mo, 10 mo), severe eczema, asthma, recurrent otitis media, subtle minor physical malformation (low anterior hairline, deep-set eyes, mildly cupped ears, down-turned corners of the mouth, a horizontal crease on the chin, broad neck and redundant skin, increased creases in the palms and deep folds bilaterally, no hearing deficits | Died at the age of 18 mo due to Staphylococcus aureus sepsis | Retinal dystrophy without pigmentation, low visual acuity, decrease visual field, persistent eczema, failure to thrive, kyphosis, mild high-foot inversion, abnormal dentition, hypopigmentation macule at right thigh (developed after transplant) | |
| Other tests with normal results | Chromosomal breakage studies, telomere length, next-generation sequencing of a panel of known 72 IBMFS genes, targeted sequencing of SBDS, urine organic acid and plasma amino acids, 4X180K oligonucleotide array (Agilent Tech), Affymetrix 6.0 Array | Chromosomal breakage studies, targeted sequencing of SBDS, RMRP, Affymetrix 6.0 Array | Chromosomal breakage studies | |
| Targeted sequencing of SBDS, RMRP, Affymetrix 6.0 Array | ||||
| Mitochondrial DNA deletion analysis (for Pearson syndrome) |
CT, computed tomography; HgF, hemoglobin F; MCV, mean corpuscular volume (red blood cells); N, normal; UK, unknown; US, ultrasound.
Quantification of cellularity in percentages was not available and commonly used clinical terms to describe bone marrow cellularity were reported to the registry. We refer to “markedly reduced” cellularity in children as <25% and “mildly reduced” cellularity as “50-75%.”
Reference levels are from ∼3 years of age onward.