Expected weight gain for children with microcephalic osteodysplastic primordial dwarfism type II

To the Editor: Microcephalic osteodysplastic primordial dwarfism type II (MOPDII; OMIM #210720), first described by Majewski, Ranke, and Schinzel (1982), is the most common distinctive diagnostic entity within the group of microcephalic primordial dwarfism syndromes (Hall, Flora, Scott, Pauli, & Tanaka, 2004; Klingseisen & Jackson, 2011; Rauch, 2011). Aside from the classic features of severe preand post-natal growth failure together with microcephaly, individuals with MOPDII have a characteristic skeletal dysplasia (Hall et al., 2004; Willems et al., 2009) with a specific hip pathology (Karatas et al., 2014), abnormal dentition (Kantaputra et al., 2011), an increased risk for cerebrovascular disease (Bober et al., 2010; Brancati, Castori, Mingarelli, & Dallapiccola, 2005; Waldron et al., 2009), and insulin resistance (Huang-Doran et al., 2011). MOPDII has autosomal recessive inheritance and is caused by mutations in the pericentrin (PCNT) gene (Rauch et al., 2008). Typically, infants born small for gestational age are fed aggressively in an attempt to improve growth (Hall et al., 2004). However, given the underlying nature of MOPDII, typical growth velocities are unattainable. It is our experience that many individuals with MOPDII have gastrostomy tubes recommended, if not placed, in the neonatal period, given their exceedingly slow weight gain. In order to help guide management of the child with MOPDII, we previously published detailed growth curves for height, weight, and head circumference, as well as weight for height curves to assess proportions, for 26 individuals with MOPDII with PCNT mutations or demonstrated absence of PCNT protein (Bober et al., 2012). It has since become apparent that a valuable metric to help guide the nutritional management of an infant with MOPDII is having an appropriate expectation of weight gain per day by age. We recently generated this type of curve for a different dysplasia diagnosis, and it has proven quite helpful in the clinical setting (Duker et al., 2017). To that end, we are including here the grams per day expectations from birth to 17 years for individuals with MOPDII, using the same ascertainment of patients published in Bober et al. (2012). To date, 32 patients in the Nemours IRB approved Primordial Dwarfism Registry have molecular confirmation of their MOPDII diagnosis as well as weight measurements for analysis. Longitudinal weight data comprising 446 distinct datum from 32 patients (15 female, 17male) ranging in age frombirth to 28 yearswere analyzed. Data point count binned by year is noted in Supplemental Figure S1. All data utilized were from prior to the initiation of any growth hormone supplementation. Weight versus age data were resampled with replacement 100 times and fit using a locally weighted regression model (LOESS) with a span of 0.99 (Cleveland, Grosse, & Shyu, 1992). The derivative of this fit was calculated using a central difference method, and then re-smoothed using LOESS with a span of 0.90. Span parameters which dictated the degree of smoothing in the model were chosen to ensure monotonic increases or decreases in the data and smooth out local effects that might imply non-existent decreases in weight as age increased. The resultant weight-velocity curve was the mean of the bootstrapped curves surrounded by a band indicating the bootstrapped standard deviation. This was then plotted both from birth to 17 years. Because later data was from a single subject whose mean weight was below the group average, this caused an unrealistic down-turn in the weight versus age graph. All statistics were done using R statistical software (R Core Team, 2017). As noted in Figure 1, and contrasting with a typical neonate, infants with MOPDII have an expected weight gain of approximately 2 g/d throughout their first year of life. As the figure continues to