PURA-related NDD has been recently recognized as a cause of ID with advances in genetic technologies. To date, 11 patients with 5q31.3 deletion syndrome and 85 patients with PURA syndrome, including our patients, have been reported. The universal clinical features of PURA-NDDs are moderate to severe ID with verbal language delay and profound neonatal hypotonia . We confirmed that all of our patients with PURA-NDDs displayed hypotonia in the neonatal period. Their developmental milestones regarding gross motor and language were severely retarded beyond the neonatal period. All patients in our cohort were not able to attain independent gait even with appropriate physical therapy, similar to most previously reported patients (1). Some earlier studies described patients with PURA variants who were able to achieve their first steps from 28 months to 7 years and even maintained independent gait at age 20 [13, 16]. Language delays were evident in all patients, as they were nonverbal. Cinquina et al. summarized other associated clinical features, including skeletal, cardiac, urogenital, and dermatological abnormalities, in PURA syndrome . They mentioned that distinctive facial traits were reported in 84.5% of patients with PURA syndrome. As demonstrated by computational analysis, dysmorphic facial features include myopathic faces, full cheeks, high anterior hairlines, shorter palpebral fissures, and prominent philtrums . Concordant with earlier studies, 71.4% of our patients had distinctive facial features with typically open-tented upper vermillion, long philtrum, and anteverted nares. Ophthalmological problems such as nystagmus, poor visual fixation and tracking were also commonly associated in our patients. The prevalence was higher than that in the pre-existing literature, in which strabismus was an accompanying symptom in approximately 30-40% of individuals with PURA-NDDs [6, 13, 14]. Exaggerated startling responses were associated in 43% of patients, which was similar to previous reports . Endocrine abnormalities such as aberrant sex and thyroid hormone levels have also been reported in PURA-NDD [13, 21]. Bonaglia et al. presented a 26-year-old female who had a 5q31.2q31.3 microdeletion and had pubertal delay and primary amenorrhea . Additionally, Reijnders et al. reported two patients (Patient No.1 and Patient No.23) who had hypogonadotrophic hypogonadism that required medical treatment . Very recently, Boczek et al. published a case study of a 20-year-old male with short stature and delayed puberty who had hypogonadotropic hypogonadism requiring supplementation . At present, the majority of reported PURA-NDD patients are in their childhood, and little is known about endocrine problems beyond the age of puberty in PURA-NDDs. Endocrine problems related to sex hormones could be one of the clinical features in patients with PURA-NDDs and would be worth monitoring in patient care and exploring in future studies.
PURA-NDD was first described and identified by microarray-based CGH . As WES has been gradually expanded in the clinical setting, a number of PURA syndromes caused by de novo pathogenic variants have been increasingly reported [5, 6, 14]. PURA-NDDs do have core clinical phenotypes. Reijnders et al. depicted a striking example of diagnosing PURA syndrome in a neonate through targeted Sanger sequencing based on clinical phenotype . However, there is still a broad spectrum of clinical features and variability in clinical severity within PURA-NDD. These variabilities challenge the diagnostic process even for specialized clinicians. When we retrospectively reviewed the diagnostic process, more than half of patients underwent evaluations under the impression of central or neuromuscular hypotonia such as Prader-Willi syndrome, inherited myopathies and metabolic disorders in their neonatal period due to hypotonia, feeding difficulty, and respiratory problems. In their infancy, more than 70% of patients had muscle biopsies and electrophysiological studies to rule out neuromuscular disorders. Reviewing other works, clinicians frequently performed single-gene testing of Prader-Willi syndrome, Fragile X syndrome (FMR1), metabolic testing and occasional mitochondrial studies [1, 16]. Similar to our study, muscle biopsies and myotonic dystrophy testing were also frequently performed. Due to respiratory problems or irregular breathing patterns, a central hypoventilation panel or PHOX2 sequencing was applied in a few patients. We suggest that PURA-NDDs need to be considered as a differential diagnosis in patients who have severe neonatal hypotonia with feeding and respiratory difficulty, followed by profound global developmental delay, particularly in verbal expression.
We did not observe differences in the severity of clinical features between individuals with 5q31.3 microdeletions and single-nucleotide pathogenic variants in PURA. Our study supports that PURA is a primary causative gene for the core neurodevelopmental features of 5q31.3 microdeletion syndrome . Similar to previous studies, we could not find correlations between the types or locations of variants and clinical severity and variability [13, 23]. Patient No.5 had two pathogenic variants, and the phenotypic severity was not different from the others. This mechanism is suggested by a dominant-negative effect for structural variants and functional haploinsufficiency for truncating mutations. This might be explained by the involvement of other genetic or biological mechanisms.