Phenotypic variability and gastrointestinal manifestations/interventions for growth in NAA10‐related neurodevelopmental syndrome

Abstract

Our study of 61 children with NAA10‐related neurodevelopmental syndrome, an X‐linked disorder due to NAA10 gene variants, demonstrated a high prevalence of growth failure, with weight and height percentiles often in the failure‐to‐thrive diagnostic range; however, dramatic weight fluctuations and phenotypic variability is evidenced in the growth parameters of this population. Although never previously explored in depth, the gastrointestinal pathology associated with NAA10‐related neurodevelopmental syndrome includes feeding difficulties in infancy, dysphagia, GERD/silent reflux, vomiting, constipation, diarrhea, bowel incontinence, and presence of eosinophils on esophageal endoscopy, in order from most to least prevalent. Additionally, the gastrointestinal symptom profile for children with this syndrome has been expanded to include eosinophilic esophagitis, cyclic vomiting syndrome, Mallory Weiss tears, abdominal migraine, esophageal dilation, and subglottic stenosis. Although the exact cause of poor growth in NAA10‐related neurodevelopmental syndrome probands is unclear and the degree of contribution to this problem by GI symptomatology remains uncertain, an analysis including nine G‐tube or GJ‐tube fed probands demonstrates that G/GJ‐tubes are overall efficacious with respect to improvements in weight gain and caregiving. The choice to insert a gastrostomy or gastrojejunal tube to aid with weight gain is often a challenging decision to make for parents, who may alternatively choose to rely on oral feeding, caloric supplementation, calorie tracking, and feeding therapy. In this case, if NAA10‐related neurodevelopmental syndrome children are not tracking above the failure to thrive (FTT) range past 1 year of age despite such efforts, the treating physicians should be consulted regarding possibly undergoing G‐tube placement to avoid prolonged growth failure. If G‐tubes are not immediately inducing weight gain after insertion, recommendations could include altering formula, increasing caloric input, or exchanging a G‐tube for a GJ‐tube by means of a minimally invasive procedure.

Evaluating possible maternal effect lethality and genetic background effects inNaa10knockout mice

“…This current study continues our analysis of the original Naa10 -/Y knockout strain of live born mice, as previously reported [21], but now genetically inbred with more than 20 backcrosses phenotypic difference in body weight where the KO mouse is noticeably smaller than the WT littermate mouse. This is similar to the human condition, as some individuals with Ogden syndrome are small in weight and have short stature, whereas a few humans develop at typical size [53].…”

“…Previous publications have reported that one of the phenotypes observed in Naa10 knockout mice is low body weight compared to their wildtype littermates (Kweon et al 2021;Lee et al 2017). A recent analysis in humans analyzed these growth defects in greater detail, which showed extensive weight fluctuations, along with the recommendation that OS individuals not tracking above the failure to thrive range past one year of age might be considered for G-tube placement to avoid prolonged growth failure (Sandomirsky et al 2023). The current study aims to characterize the development, growth and phenotypes of various mice deficient in Naa10, beginning with embryogenesis, thus extending and expanding on our prior findings (Kweon et al 2021).…”

Evaluating possible maternal effect lethality and genetic background effects in Naa10 knockout mice

“…Fig 8 shows a phenotypic difference in body weight where the KO mouse is noticeably smaller than the WT littermate mouse. This is similar to the human condition, as some individuals with Ogden syndrome are small in weight and have short stature, whereas a few humans develop at typical size [ 53 ].…”

“…Previous publications have reported that one of the phenotypes observed in Naa10 knockout mice is low body weight compared to their wildtype littermates [ 21 , 52 ]. A recent analysis in humans analyzed these growth defects in greater detail, which showed extensive weight fluctuations, along with the recommendation that OS individuals not tracking above the failure to thrive range past one year of age might be considered for G-tube placement to avoid prolonged growth failure [ 53 ]. The current study aims to characterize the development, growth and phenotypes of various mice deficient in Naa10 , beginning with embryogenesis, thus extending and expanding on our prior findings [ 21 ].…”

A four-year-old girl with pathogenic variant in the NAA10 gene and precocious puberty – case report and literature review

“…Six patients reported by the authors had precocious puberty. The study by Sandomirsky et al [15] of 61 children with Ogden syndrome, demonstrated a high prevalence of growth failure which was due to feeding difficulties in infancy, dysphagia, GERD/ silent reflux, constipation, diarrhea, bowel incontinence, eosinophilic esophagitis, cyclic vomiting syndrome, Mallory Weiss tears, abdominal migraine, esophageal dilation, and subglottic stenosis.…”