Abstract
Neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (NEDRIHF) is a very rarely reported disease. The disease is due to microdeletions in the PURA gene on chromosome 5q31. It is one of the rare causes of central hypotonia in neonates causing parental concern and anxiety. We report one such rarely diagnosed case of NEDRIHF-PURA (purine-richelement-binding protein A) syndrome.
Keywords: NEDRIHF, PURA syndrome, Central hypotonia, NEDRIHF-PURA syndrome, Purine-rich element-binding protein A
Introduction
Hypotonia at birth is often a diagnostic dilemma and a source of serious medical and parental concern. Neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (NEDRIHF) is a very rare disease – recognized only in last few decades. With the advent of newer and advanced genetic tests, only a few cases have been reported in literature. However, the exact incidence is still not known.1 We report a neonate with NEDRIHF-PURA (purine-rich element-binding protein A) syndrome.
Case report
A female neonate was delivered to a 35-year-old primigravida (a post-in vitro fertilization (IVF) conception with no known comorbidity) at term by lower segment caesarean section (indication – non-progress of labour with decreased foetal movement and foetal bradycardia). There was no history of fever with rash, diabetes, hypertension, leaking per vaginum, or chorioamnionitis in the mother. There was no antenatal history of polyhydramnios. The neonate cried immediately after birth, and the appearance, pulse, grimace, activity, and respiration (APGAR) score was 7 and 9, respectively, at 1 and 5 min. However, she was found to be floppy since birth with reduced limb movements.
In the neonatal intensive care unit (NICU), the baby was observed to be lying in the frog-legged position (hips were abducted, and knees were flexed) (Fig. 1). She had weak cry and seemed drowsy all the time. The respiratory rate was persistently low (ranging between 20 and 30). However, she maintained saturation in room air well and had no signs of respiratory distress. Other vital parameters were normal. On neurological examination, she had generalised decreased muscle tone with a ragged doll appearance on ventral suspension (Fig. 2). There was head lagging behind when pulled to sit; on scarf sign, the elbows crossed midline with the adductor angle measuring 130° and the poplitaeal angle measuring 150°, both more than the normal range for age. The neonatal reflexes, such as rooting, sucking, and Moro's, were all weak. Deep tendon jerks were, however, normal. No tongue fasciculation could be seen. There was no clinical seizure observed. There was no obvious dysmorphism. There were no signs of muscle weakness or myotonia in parents.
Fig. 1.
Frog-legged position.
Fig. 2.
Rag doll appearance on ventral suspension.
During the hospital stay, the neonate was noticed to have episodes of desaturation, which recovered on its own. After getting discharged, the neonate presented with poor feeding and required readmission at 2 weeks of age. The baby had episodes of cessation of breathing followed by bluish discolouration of lips and face and unresponsiveness requiring bag and mask ventilation. The neonate was managed with oxygen support via a heated humidified high-flow nasal cannula, and supervised feeds were given. She was gradually weaned off to room air and was discharged on expressed breast feeds by Paladai feeds.
In view of the features of central hypotonia and hypoventilation, the following investigations were done. Blood cytology revealed Hb = 19.5 g/dL, TLC = 20150/mm3, DLC = N56, L34, Platelets = 289,000. Thyroid profile was normal. Tandom mass spectrometry (TMS) and gas chromatography–mass spectrometry (GCMS) reports were negative for any inborn error of metabolism. Echocardiography was done to rule out any cardiomyopathy and was reported normal. Ultrasound abdomen was normal. Dried blood spot (DBS) for acid alpha glucosidase to rule out Pompe disease was negative. Magnetic Resonance Imaging (MRI) of the brain was reported normal and did not reveal any structural anomaly or any stigmata of asphyxia. Karyotype revealed absence of chromosomal anomaly. However, as there was a high suspicion of any congenital genetic cause, whole exome sequencing was sent. It revealed heterozygous single-base-pair deletion in exon 1 (c.531del, p.Pro178LeufsTer47) of the PURA gene (Fig. 3). This is a deleterious frameshift variant classified as pathogenic as per ACMG/AMP guidelines. Heterozygous variant in PURA gene is associated with NEDRIHF – thus explaining all the symptoms of the patient. Parental Sanger sequencing could not be performed as it was an in vitro fertilization conception with donor gamete. Parents were counselled about the nature and course of the disease. The baby has been followed-up for about 3 months, and the baby has remained floppy with no head control yet. Informed consent was obtained from parents of patient for use of images in this study.
Fig. 3.
IGV (integrated genomic viewer) depicting heterozygous variant in PURA gene.
Discussion
NEDRIHF is a disease caused by heterozygous variants in the PURA gene on chromosome 5q31. PURA “Highly conserved 322 amino acid multifunctional protein, Pur –α”, that has important roles in DNA duplication, transcription, and mRNA trafficking.2 In animal studies, Pur-α was found to be required in postnatal development of the brain and is involved in both neuronal proliferation and maturation of dendrites, and it has also been shown to be important for the transport of specific mRNA molecule to sites of translation in hippocampal neurons.3,4 Mutation in this gene is typically characterised by a wide spectrum of neuro developmental problems, including severe neuro developmental delay, epilepsy, abnormal movements, hypotonia, and learning disabilities.5 A broad variation in clinical severity has been found within PURA syndrome due to different types of variants throughout the gene.6
Most of the neonates are delivered at term and beyond. It is characterised by severe hypotonia at birth associated with respiratory difficulties including apnoea, hypoventilation, and feeding difficulties.7 Neonates may require respiratory support, even mechanical ventilation in more severe cases. Feeding often is difficult, and tube feeding has to be given at times. Significantly, many neonates have hyper somnolence and hypothermia. Some neonates have an exaggerated startle response. All individuals with PURA variants have moderate to severe intellectual disability with language and motor delay. Many variable neurological presentations such as hypotonia (truncal more evident), unstable and broad-based gait if achieved, stereotypic hand movements, seizure-like movements, or frank epilepsy are also reported. MRI of the brain in many cases have shown delayed myelination, white matter abnormalities, prominent periventricular spaces, mild parenchymal atrophy, and under-developed rostrum of the corpus callosum. Eye abnormalities such as strabismus have also been commonly reported. Along with feeding difficulty, constipation is also seen in many cases. Among other congenital structural malformation, various cardiac, respiratory, and urogenital malformations have been reported. Among dysmorphic features, myopathic face, high anterior hairline, almond-shaped palpebral fissures, and full cheeks have been commonly reported.5,7
In our case, in view of hypoventilation, increased somnolence, feeding difficulty, and preserved reflexes, in a case of generalised hypotonia, we evaluated this as a case of central hypotonia. There was no obvious dysmorphism and karyotype-ruled-out Down syndrome. Normal thyroid profile ruled out congenital hypothyroidism. Normal TMS/GCMS ruled out inborn errors of metabolism. Normal echocardiogram with normal DBS ruled out Pompe disease. MRI of the brain ruled out any structural anomaly, stigmata of post asphyxia changes, or molar tooth sign (ruling out Joubert syndrome). The whole exome genetic testing confirmed the case to be of NEDRIHF due to PURA gene variant.
This syndrome unfortunately has no treatment, and the affected children suffer from mental retardation, language impairment, motor retardation, gait and movement abnormalities, and epilepsy at a later age.1
We thus report a rare case of NEDRIHF – PURA scarcely reported so far. The aim of reporting this case is to sensitize the readers of a relatively rare syndrome that should be kept in mind when evaluating for a case presenting with hypotonia, hypoventilation, and feeding difficulties once the other common causes have been ruled out.
Patients/ Guardians/ Participants consent
Patients informed consent was obtained.
Ethical clearance
Not Applicable.
Source of support
Nil.
Disclosure of competing interest
The authors have none to declare.
Acknowledgements
None.
References
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