Table 1.
Clinical Findings in Individuals with Bi-allelic Alterations in RINT1 (GenBank: NM_021930)
| Proband 1 | Proband 2 | Proband 3 | |
|---|---|---|---|
| Maternal | c.1853_1858del6 (p.Val618_Lys619del) | c.1102G>A (p.Ala368Thr) | c.1109T>C (p.Leu370Pro) |
| Paternal | c.1333+1G>A (p.?) | c.1333+1G>T (p.?) | c.1333+1G>A (p.?) |
| Ancestry | mixed European | East Asian | Eastern European |
| Sex | male | female | female |
| Birth history | |||
| Gestation | born at 33 6/7 weeks | born at term | born at term |
| Birth weight | 2.53 kg (78th percentile) | 3.70 kg (83th percentile) | 2,75 kg (5th percentile) |
| Length | 44.5 cm (49th percentile) | 54.0 cm (99th percentile) | not available |
| Head circumference | 33.5 cm (92nd percentile) | normal | not available |
| Neonatal jaundice | yes, peak bilirubin 11.8 mg/dL (direct bilirubin 0.4 mg/dL) at 2 days old; phototherapy | none | none |
| Dysmorphisms | talipes equinovarus at birth requiring casting | none | none |
| Newborn screen | borderline elevated methionine, normal with follow-up testing | unremarkable | unremarkable |
| Weight at last evaluation | normal | normal | normal |
| Height at last evaluation | <3rd percentile | <3rd percentile | 75% percentile |
| Development | normal | normal | normal |
| Age at first ALF episode | 8 mo | 10 mo | 3 y |
| Age at last assessment | died at 3 y 2 mo | 8 y 11 mo | 7 y 6 mo |
| Episodes of ALF or acutely elevated transaminases | 5 | 8 | 4 |
| Age at last episode of ALF/acutely elevated transaminases | 3 y | 6 y 8 mo | 7 y 3 mo |
| Acute liver episodes concurrent with illness or fever/total number of episodes | 5/5 | 8/8 | 4/4 |
| Suspected triggers of episodes | fever or infection | fever with vaccination or infection | illness and fever |
| Hepatomegaly | + | + | mild (+1–2 cm from RCM) |
| Splenomegaly | + (inconsistent) | − | 2 cm (in acute setting) |
| Hepatomegaly between episodes | + | + | none |
| Laboratory findings during an ALF episode | |||
| Glucose | 9 mg/dL (ref: 70–140 mg/dL) | 0.2 mmol/L (ref: 3.9–5.8 mmol/L) | 1.7 mmol/L |
| ALT | 1,915 U/L (ref: 7–55 U/L) | 3,214 U/L (ref: 8–40 U/L) | ca. 2,000 U/L (ref: 0–19 U/L) |
| AST | 5,956 U/L (ref: 8–60 U/L) | 1,885 U/L (ref: 10–55 U/L) | ca. 2,000 U/L (ref: 0–33 U/L) |
| Total bilirubin | 7.6 mg/dL (ref: ≤ 1 mg/dL) | 3.1 mg/dL (ref: 0.1–1.2 mg/dL) | 6.5 mg/dL (ref: 0–0.3 mg/dL) |
| Direct bilirubin | 5.6 mg/dL (ref: 0–0.3 mg/dL) | 2.5 mg/dL (ref: 0–0.4 mg/dL) | 5.6 mg/dL (ref: 0–0.1 mg/dL) |
| Prothrombin time | 70.6 s (ref: 9.4–12.5 s) | 99 s (ref: 11.5–14.9 s) | 160 s |
| INR | 7.0 (ref: 0.9–1.1) | 5.5 (ref: 0.8–1.2) | >11 (ref: 0.8–1.2) |
| Highest AST/ALT (U/L) during ALF | 5,956/1,915 (1st episode; 8 mo) | 3,823/8,318 (3nd episode; 2y2m) | >16,646/8,429 IU/L |
| Lowest AST/ALT (U/L) between episodes | 122/282 (2 y) | 25/44 (6 y 5 mo) completely normalized by 8 yo | normal |
| Age at liver biopsy | 10 mo 8 d | 1 y 9 mo | 7 y 4 mo |
| Liver biopsy findings | |||
| Steatosis | + | + | − |
| Fibrosis | + | − | − |
| Increase in Kupffer cells | − | − | + |
| AST/ALT (U/L) at liver biopsy | 458/431 (12 days prior to biopsy) | 28/43 (2 days prior to biopsy) | 14/30 (2 days prior liver biopsy) |
| Retroperitoneal ultrasound | normal | normal | hyperechoic cortex of both kidneys |
| Echocardiogram | normal | normal | satisfactory biventricular function; minimal aortic insufficiency; elevated R side pressures |
| Skeletal findings | |||
| Hypoplastic vertebrae | + | + | + |
| Beaked vertebrae | + | + | + |
| Irregular vertebrae | + | + | + |
| Platyspondyly | + | − | − |
| Acetabular abnormalities | + | + | − |
| Abnormal femoral head epiphysis | + | + | + |