Prenatal-Onset Growth Restriction and Microcephaly in Individuals with TOP3A Mutations
Prenatal growth restriction was evident from the substantially reduced birth weight in all individuals (mean weight −2.6 ± 0.9 SD; Table 2 and Figure 1A). Postnatally, weight (mean −4.8 ± 1.8 SD), height (mean −3.9 ± 1.0 SD), and occipital-frontal circumference (mean −4.0 ± 1.2 SD) were significantly reduced. Growth parameters were similar to those previously reported for Bloom syndrome (mean birth weight −3.7 ± 1.2 SD, mean postnatal weight −3.8 ± 2.1 SD, and mean height −3.9 ± 1.1 SD).21 Although multiple café-au-lait patches were present in some individuals with TOP3A mutations, the classical erythematous malar facial rash was not apparent, and there were no reports of malignancies (although none had yet reached adulthood; Table 3 and Figure 1B).
Figure 1 Variants in TOP3A Are Associated with Prenatal-Onset Growth Retardation and Microcephaly
(A) Morphometric data for TOP3A individuals. A global reduction in growth is evident from before birth. Z scores (standard deviations from population mean for age and sex) for birth weight (Wgt), postnatal weight, height (Hgt), and occipital-frontal circumference (OFC). Dashed lines indicate the 95% confidence interval for the general population. Black circles indicate data points for individuals with TOP3A mutations. For comparison, gray bars indicate the mean value for cohorts of 89 (birth weight), 47 (current weight), and 52 (current height) subjects with Bloom syndrome.21
(B) Photographs of facial features of individuals with TOP3A mutations.
Table 2 Growth Parameters of Individuals with TOP3A and RMI1 Mutations Z scores are the standard deviation from population mean for age and sex. The following abbreviation is used: NA, not available. a Adjusted for gestation. b Growth-hormone treatment from 4 years, 3 months of age to 5 years, 11 months of age showed no response. c Previously reported individual with adult-onset mitochondrial disease (ataxia and progressive external ophthalmoplegia).32
Table 3 Clinical Phenotype of Individuals with TOP3A and RMI1 Mutations Abbreviations are as follows: CDH, Congenital dislocation of hip; CMAMMA, combined malonic and methylmalonic aciduria (MIM: 614265) due to ACSF3 (MIM: 614245) mutations; HCM, hypertrophic cardiomyopathy; NA, not available; and PEO, progressive external ophthalmoplegia. a Expressive speech delay only. b All individuals are younger than 15 years old; in Bloom syndrome, neoplasia typically manifests in early adulthood. c Recurrent otitis media and tonsillitis, leading to tonsillectomy. d Reccurent upper-respiratory-tract infections and oral thrush. e Mild left-ventricle dilatation. f Anemia due to beta-thalassemia trait.