Growth Patterns In Pura Syndrome: Failure To Thrive And Short Stature

Introduction

PURA syndrome is a rare genetic condition that affects brain development and often causes low muscle tone (hypotonia), developmental delays, and seizures. Another major issue for many with PURA syndrome is growth problems, including failure to thrive and short stature. These symptoms can significantly affect a child's health and development.

This article brings together data from several case reports and studies to explain how and why children with PURA syndrome may struggle with growth. We’ll explore what’s known about poor weight gain and short height and the role that feeding problems, hormones, and skeletal differences play. We’ll also look at how a team-based medical approach can help manage these issues.

Understanding growth issues in PURA syndrome

PURA syndrome results from changes (mutations) in the PURA gene, located on chromosome 5. While the condition is best known for affecting the brain, recent research shows that growth concerns are also common. Studies have reported feeding problems, delayed bone growth and short stature in some children with PURA syndrome.1,2

Common growth concerns

Failure to thrive

“Failure to thrive” means a child isn’t gaining weight or growing as expected. In PURA syndrome, this is a common problem, primarily due to feeding difficulties. Many babies with PURA syndrome have impaired suck and swallow reflexes, and troubles managing saliva, all due to low muscle tone.1 More than 70–80% of affected children present serious feeding challenges.1,3

Often, these problems require medical feeding support such as a feeding tube.4,5 Without enough calories, children may fall behind on growth milestones. In some reports, the need for nutritional support indicated that these children weren’t thriving.1,6

Short stature

Short stature – being significantly shorter than average for age and gender – has been noted in some children with PURA syndrome. One study found that 16-19% of children had a height above 2.5 standard deviations below the average.1 Some of these kids also had delayed bone age, meaning their bones developed more slowly than expected.2,7

In a case report, an 18-year-old was growing normally at first but stopped gaining height and weight around age 7. By age 20, his bones were at the developmental stage of an 11-year-old.2,7 Other reports show that not all children with failure to thrive are short – some maintain normal height but still struggle with weight.8

What causes growth issues in PURA syndrome?

Feeding challenges due to hypotonia

Most babies with PURA syndrome are born with very low muscle tone. This affects their ability to feed normally and efficiently, leading to inadequate calorie intake. Some also experience digestive issues, making feeding even harder.1,3

Hormonal and endocrine differences

Some children with PURA syndrome show signs of hormonal imbalances that can affect growth. For instance, one study found that nearly 47% of patients had low vitamin D levels, which is essential for bone health.1,6 Other hormonal problems – like irregular thyroid or sex hormone levels – have also been reported.2 In some children, these imbalances lead to delayed puberty and slow bone development.2,7

Skeletal and muscular issues

Many children with PURA syndrome also have differences in their bones and muscles. These include low bone density, scoliosis (curved spine), and hip problems.1,4 Such issues may increase the risk for fractures and limit physical activity, both of which can affect normal growth.4,7

Not all children with PURA syndrome grow in the same way. Some may be very small overall, while others grow tall but gain little weight. This variation could depend on the specific genetic mutation or other factors like the degree of hypotonia or hormone function.9,10 Even with similar genetic changes, kids can show very different growth outcomes.10,11

Real world case examples

Delayed growth and puberty: One young man with a PURA gene variant (c.190A>T, p.Lys64\) had very short stature and a bone age nearly a decade behind his actual age. Though his hormone levels were mostly normal, a borderline low IGF1 level suggested that growth hormone pathways might be involved. His weight and height had plateaued after the age of 7 2,7

Low weight, normal height: Another case described a child whose weight dropped from the 90th to below the 5th percentile, while height stayed within a normal range. This shows that weight can be affected without changes in height

Short stature in children: In some paediatric studies, up to 19% of children with PURA syndrome were significantly shorter than average.1,13 Many also had digestion problems like acid reflux or constipation, which can limit food intake and nutrient absorption 1,5

How doctors manage growth problems

Managing growth issues in PURA syndrome requires a team approach. Doctors, dietitians, therapists, and endocrinologists all play a role.

Nutritional support: Because feeding problems are so common, early and ongoing nutritional assessments are crucial. Some children may need tube feeding to make sure they get enough calories 3,4

Regular growth monitoring: Tracking weight, height, and body mass index (BMI) helps doctors catch problems early. Special growth charts and routine checkups can guide interventions

Endocrine evaluation: For kids who are very short or hitting puberty late, doctors may recommend hormone testing. If hormone levels are off, treatments like supplementation may be considered 2,7

Physical therapy: Therapy to improve muscle tone and movement can indirectly support growth by promoting bone health and physical activity 2,4

A multidisciplinary approach is essential. Combining nutrition, hormonal care, and physical therapy can help children reach their full potential.1,5

Summary

Growth problems in PURA syndrome are complex and can look very different from one child to another. While feeding difficulties and low muscle tone are key factors, hormone imbalances and bone differences may also play a role. Studies suggest that short stature affects 16-19% of children with PURA syndrome, and weight issues are even more common.

There’s no one-size-fits-all solution. Each child needs an individualised care plan that includes nutrition, hormonal assessments, and physical therapy. Importantly, ongoing research is helping to clarify how genetic differences impact growth and how best to support affected children.

With early recognition and the right team of specialists, families and providers can work together to give kids with PURA syndrome the best chance at healthy development and quality of life.

References

Liu Y, Liu R, Xu T, Zhou YX, Zhang SC. Neonatal PURA syndrome: a case report and literature review. Transl Pediatr. 2021 Jan;10(1):194–203. Available from: https://pubmed.ncbi.nlm.nih.gov/33633953/

Kim HJ, Park CI, Lim JW, Lee GM, Cho E, Kim HJ. Phenotypic analysis of Korean patients with abnormal chromosomal microarray in patients with unexplained developmental delay/intellectual disability. Yonsei Med J. 2018 May 1;59(3):431–7. Available from: https://pubmed.ncbi.nlm.nih.gov/29611406/

Boczek NJ, Macke EL, Kemppainen J, Klee EW, Renaud DL, Gavrilova RH. Expansion of PURA-related phenotypes and discovery of a novel PURA variant: a case report. Child Neurol Open. 2020 Oct 14;7:2329048X20955003. Available from: https://pubmed.ncbi.nlm.nih.gov/33117858/

Qiao Y, Bagheri H, Tang F, Badduke C, Martell S, Lewis SME, et al. Exome sequencing identified a de novo mutation of PURA gene in a patient with familial Xp22.31 microduplication. Eur J Med Genet. 2019 Feb;62(2):103–8. Available from: https://pubmed.ncbi.nlm.nih.gov/29908350/

Tanaka AJ, Bai R, Cho MT, Anyane‑Yeboa K, Ahimaz P, Wilson AL, et al. De novo mutations in PURA are associated with hypotonia and developmental delay. Cold Spring Harb Mol Case Stud. 2015 Oct;1(1):a000356. Available from: https://pubmed.ncbi.nlm.nih.gov/27148565/

Reuter MS, Chaturvedi RR, Liston E, Manshaei R, Aul RB, Bowdin S, et al. The Cardiac Genome Clinic: implementing genome sequencing in pediatric heart disease. Genet Med. 2020 Jun;22(6):1015–24. Available from: https://pubmed.ncbi.nlm.nih.gov/32037394/

Reijnders MRF, Janowski R, Alvi M, Self JE, van Essen TJ, Vreeburg M, et al. PURA syndrome: clinical delineation and genotype–phenotype study in 32 individuals with review of published literature. J Med Genet. 2018 Feb;55(2):104–13. Available from: https://pubmed.ncbi.nlm.nih.gov/29097605/

Molitor L, Bacher S, Burczyk S, Niessing D. The molecular function of PURA and its implications in neurological diseases. Front Genet. 2021 Mar 11;12:638217. Available from: https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.638217/full

Lee BH, Reijnders MRF, Abubakare O, Tuttle E, Lape B, Minks KQ, et al. Expanding the neurodevelopmental phenotype of PURA syndrome. Am J Med Genet A. 2018 Jan;176(1):56–67. Available from: https://pubmed.ncbi.nlm.nih.gov/29150892/

Jezela‑Stanek A, Ciara E, Jurkiewicz D, Kucharczyk M, Jędrzejowska M, Chrzanowska KH, et al. The phenotype‑driven computational analysis yields clinical diagnosis for patients with atypical manifestations of known intellectual disability syndromes. Mol Genet Genomic Med. 2020 Sep;8(9):e1263. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/mgg3.1263

Fukuda Y, Kudo Y, Saito M, Kaname T, Oota T, Shoji R. Expanding the PURA syndrome phenotype with manifestations in a Japanese female patient. Hum Genome Var. 2022 Apr 19;9(1):1–5. Available from: https://www.nature.com/articles/s41439-022-00189-7

Choi SA, Lee HS, Park TJ, Park S, Ko YJ, Kim SY, et al. Expanding the clinical phenotype and genetic spectrum of PURA‑related neurodevelopmental disorders. Brain Dev. 2021 Oct;43(9):912–8. Available from: https://pubmed.ncbi.nlm.nih.gov/34116881/

Aitken S, Firth HV, McRae J, Halachev M, Kini U, Parker MJ, et al. Finding diagnostically useful patterns in quantitative phenotypic data. Am J Hum Genet. 2019 Nov;105(5):933–46. Available from: https://pubmed.ncbi.nlm.nih.gov/31607427/