Clinical, imaging, and histopathologic findings in 3 patients with a pathogenic RBSN variant
| . | Patient VI.2 . | Patient VI.3 . | Patient VI.4 . |
|---|---|---|---|
| Phenotype | Female | Female | Female |
| Chromosomes | 46,XY | 46,XX | 46,XX |
| CMA | Normal (BG v.5 and 400 000 oligonucleotide research array) | Normal (BG v.6.4) | Normal (BG v.8.3) |
| Growth | Age, 11 mo; height, 25%; weight, 75%; OFC, 25%-50% | Age, 9 y 2 mo; height, <1%; weight, 76%; OFC, 18% | Age, 4 y 11 mo; height, <1%; weight, 57%; OFC: 5% |
| Facial features | Narrow bi-temporal diameter, metopic prominence, sloping forehead, upslanting palpebral fissures, epicanthal folds, bulbous nose, depressed nasal tip | Prominent nasal bridge, low-set posteriorly rotated ears, retromicrognathia, high-arched palate | Bi-temporal narrowing, tubular nose, prominent columella |
| Hematologic | SCN transiently responsive to intermediate-dose filgrastim, PB NRBCs, progressive anemia and thrombocytopenia, hypercellular bone marrow with severe reticulin fibrosis and myeloid hyperplasia, extramedullary hematopoiesis (liver, spleen, kidneys, lymph nodes) on PME | SCN without maturation arrest, refractory to filgrastim, transfusion-dependent anemia, variable thrombocytopenia including at birth and with infection, PB NRBCs, normocellular bone marrow with moderate to severe reticulin fibrosis and maturing trilineage hematopoiesis | SCN refractory to filgrastim, moderate anemia at birth (variably present subsequently), PB NRBCs, hypercellular bone marrow with moderate to severe reticulin fibrosis and maturing trilineage hematopoiesis |
| Ophthalmologic | Poor visual response, microphthalmia, hypoplastic irides, microcornea, blepharophimosis, absent retinal vessels, aplastic optic nerves | Poor visual response, microphthalmia, microcornea, blepharophimosis, aplastic optic nerves | Poor visual response, microphthalmia, aniridia with iris coloboma, blepharophimosis, dysplastic optic nerves, absent retinal vessels |
| Neurologic | Increased muscle tone in the lower extremities, DTRs 2+, poor head control | Increased muscle tone in the 4 extremities, DTRs 3+, normal electroencephalogram | Joint restriction, hypotonia, diminished strength, muscle atrophy, normal DTRs |
| Brain MRI | Prominent supratentorial ventricles, sulci, and cisterns, widened sylvian fissures, thin corpus callosum, cerebral atrophy, severe optic nerve and chiasm hypoplasia, diffuse expansion of diploic calvarial marrow space | Perinatal intraparenchymal and subarachnoid hemorrhages, supratentorial volume loss, thin corpus callosum, mild myelin maturation delay, hypoplasia of the optic nerve, chiasm, and optic tract, bone enhancement likely related to myelofibrosis | N/A |
| Respiratory | Tracheomalacia | Tracheomalacia | Normal |
| Cardiovascular | Mild cardiomegaly on PME | Small PDA, redundant atrial septum | Small PFO, small secundum ASD |
| Gastrointestinal | Gastrostomy feeding only, gastroesophageal reflux, hepatosplenomegaly with extramedullary hematopoiesis on PME, accessory spleen | Gastrostomy feeding only, mild esophageal dysmotility, hepatomegaly likely related to extramedullary hematopoiesis | Gastrostomy feeding only, hepatomegaly likely related to extramedullary hematopoiesis |
| Orthopedic | Osteopenia, congenital hip dysplasia, tapered fifth finger | Osteopenia, femur fracture, bilateral hip dysplasia, clinodactyly, delayed bone age (2-3 y), advanced bone age (6-7 y) | Delayed bone age (−3 standard deviations below mean), bilateral hip dysplasia |
| Genitourinary | Hypoplastic labia minora and majora, underdeveloped genital tubercle, anteriorly placed anus, streak gonads, uterine didelphys, and double vagina on PME, nephromegaly with extramedullary hematopoiesis on PME | Nephromegaly, likely related to extramedullary hematopoiesis | Normal |
| Endocrine | Mild adrenal cortical lipid depletion and pituitary hypoplasia on PME, elevated FSH and LH for age, normal testosterone | Elevated FSH for age | Normal |
| Audiological | Bilateral mild to moderate high-frequency sensorineural hearing impairment | Normal | N/A |
| Immunologic | Frequent infections (Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Candida albicans, influenza A virus, respiratory syncytial virus) | Normal IgG, IgA, IgM, and IgE, normal CH50 activity, normal numbers and ratios of CD4+ and CD8+ T cells and CD19+ B cells, NK cells and CD4+/CD45RA+ naïve T cells increased in absolute number with normal ratio, CD4+/CD45RO+ memory cells low in absolute number and ratio | Frequent urinary tract infections |
| Metabolic | Hypertriglyceridemia (249-335 mg/dL) | Hypertriglyceridemia (155-1086 mg/dL) | Hypertriglyceridemia (176-296 mg/dL) |
| Development/ cognition | Global developmental delay | At 9 y, severe intellectual disability, nonverbal, nonambulatory | At 5 y, severe intellectual disability, nonverbal, nonambulatory |
| . | Patient VI.2 . | Patient VI.3 . | Patient VI.4 . |
|---|---|---|---|
| Phenotype | Female | Female | Female |
| Chromosomes | 46,XY | 46,XX | 46,XX |
| CMA | Normal (BG v.5 and 400 000 oligonucleotide research array) | Normal (BG v.6.4) | Normal (BG v.8.3) |
| Growth | Age, 11 mo; height, 25%; weight, 75%; OFC, 25%-50% | Age, 9 y 2 mo; height, <1%; weight, 76%; OFC, 18% | Age, 4 y 11 mo; height, <1%; weight, 57%; OFC: 5% |
| Facial features | Narrow bi-temporal diameter, metopic prominence, sloping forehead, upslanting palpebral fissures, epicanthal folds, bulbous nose, depressed nasal tip | Prominent nasal bridge, low-set posteriorly rotated ears, retromicrognathia, high-arched palate | Bi-temporal narrowing, tubular nose, prominent columella |
| Hematologic | SCN transiently responsive to intermediate-dose filgrastim, PB NRBCs, progressive anemia and thrombocytopenia, hypercellular bone marrow with severe reticulin fibrosis and myeloid hyperplasia, extramedullary hematopoiesis (liver, spleen, kidneys, lymph nodes) on PME | SCN without maturation arrest, refractory to filgrastim, transfusion-dependent anemia, variable thrombocytopenia including at birth and with infection, PB NRBCs, normocellular bone marrow with moderate to severe reticulin fibrosis and maturing trilineage hematopoiesis | SCN refractory to filgrastim, moderate anemia at birth (variably present subsequently), PB NRBCs, hypercellular bone marrow with moderate to severe reticulin fibrosis and maturing trilineage hematopoiesis |
| Ophthalmologic | Poor visual response, microphthalmia, hypoplastic irides, microcornea, blepharophimosis, absent retinal vessels, aplastic optic nerves | Poor visual response, microphthalmia, microcornea, blepharophimosis, aplastic optic nerves | Poor visual response, microphthalmia, aniridia with iris coloboma, blepharophimosis, dysplastic optic nerves, absent retinal vessels |
| Neurologic | Increased muscle tone in the lower extremities, DTRs 2+, poor head control | Increased muscle tone in the 4 extremities, DTRs 3+, normal electroencephalogram | Joint restriction, hypotonia, diminished strength, muscle atrophy, normal DTRs |
| Brain MRI | Prominent supratentorial ventricles, sulci, and cisterns, widened sylvian fissures, thin corpus callosum, cerebral atrophy, severe optic nerve and chiasm hypoplasia, diffuse expansion of diploic calvarial marrow space | Perinatal intraparenchymal and subarachnoid hemorrhages, supratentorial volume loss, thin corpus callosum, mild myelin maturation delay, hypoplasia of the optic nerve, chiasm, and optic tract, bone enhancement likely related to myelofibrosis | N/A |
| Respiratory | Tracheomalacia | Tracheomalacia | Normal |
| Cardiovascular | Mild cardiomegaly on PME | Small PDA, redundant atrial septum | Small PFO, small secundum ASD |
| Gastrointestinal | Gastrostomy feeding only, gastroesophageal reflux, hepatosplenomegaly with extramedullary hematopoiesis on PME, accessory spleen | Gastrostomy feeding only, mild esophageal dysmotility, hepatomegaly likely related to extramedullary hematopoiesis | Gastrostomy feeding only, hepatomegaly likely related to extramedullary hematopoiesis |
| Orthopedic | Osteopenia, congenital hip dysplasia, tapered fifth finger | Osteopenia, femur fracture, bilateral hip dysplasia, clinodactyly, delayed bone age (2-3 y), advanced bone age (6-7 y) | Delayed bone age (−3 standard deviations below mean), bilateral hip dysplasia |
| Genitourinary | Hypoplastic labia minora and majora, underdeveloped genital tubercle, anteriorly placed anus, streak gonads, uterine didelphys, and double vagina on PME, nephromegaly with extramedullary hematopoiesis on PME | Nephromegaly, likely related to extramedullary hematopoiesis | Normal |
| Endocrine | Mild adrenal cortical lipid depletion and pituitary hypoplasia on PME, elevated FSH and LH for age, normal testosterone | Elevated FSH for age | Normal |
| Audiological | Bilateral mild to moderate high-frequency sensorineural hearing impairment | Normal | N/A |
| Immunologic | Frequent infections (Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Candida albicans, influenza A virus, respiratory syncytial virus) | Normal IgG, IgA, IgM, and IgE, normal CH50 activity, normal numbers and ratios of CD4+ and CD8+ T cells and CD19+ B cells, NK cells and CD4+/CD45RA+ naïve T cells increased in absolute number with normal ratio, CD4+/CD45RO+ memory cells low in absolute number and ratio | Frequent urinary tract infections |
| Metabolic | Hypertriglyceridemia (249-335 mg/dL) | Hypertriglyceridemia (155-1086 mg/dL) | Hypertriglyceridemia (176-296 mg/dL) |
| Development/ cognition | Global developmental delay | At 9 y, severe intellectual disability, nonverbal, nonambulatory | At 5 y, severe intellectual disability, nonverbal, nonambulatory |
ASD, atrial septal defect; BG, Baylor Genetics Laboratory; CH50, 50% hemolytic complement activity; CMA, chromosomal microarray analysis; DTR, deep tendon reflex; FSH, follicle-stimulating hormone; Ig, immunoglobulin; LH, luteinizing hormone; MRI, magnetic resonance imaging; N/A, not assessed; NK, natural killer; OFC, occipital frontal circumference; PB NRBC, peripheral blood nucleated red blood cell; PDA, patent ductus arteriosus; PFO, patent foramen ovale; PME, postmortem examination; SCN, severe congenital neutropenia.