A case of PURA syndrome in a newborn child (neurodevelopmental disorder syndrome with neonatal respiratory failure, hypotension and feeding difficulties; nEDRIHf(OMIM 616158))

Introduction

PURA syndrome is an extremely rare new congenital genetic disorder that affects the nervous system and is characterized by a delay in physical development, in particular motor skills such as walking; mental retardation, delayed speech development, neonatal hypotonia, excessive sleepiness, epilepsy, and other abnormalities [1][2]. This syndrome is caused by mutations in the PURA gene, on chromosome 5. It is inherited in an autosomal dominant manner [3]. Purα protein is especially important for normal brain development and neuron growth and division. The disease was first described in the medical literature in 2014. To date, 72 children have this diagnosis. However, the increasing implementation of the latest "gene sequencing" technology is expected to bring about an augmentation of the amount of diagnosed cases within a few years. According to the literature, it accounts for less than 1% of cases of development delay. Children with PURA syndrome may learn to walk later than their age mates but many of them will never be able to walk. Expressive language skills (vocabulary and speech production) tend to be more affected than receptive language skills (the ability to understand speech). PURA syndrome in newborns and infants in the first months of life is characterized by very weak muscle tone and feeding difficulties in the form of difficulty swallowing (dysphagia), which may persist throughout life. In addition, newborns and children in their first year of life may be excessively sleepy and have a low body temperature; they may experience apnea attacks or episodes of hypoventilation. These breathing problems usually resolve after 1 year [2].

Certain authors also indicate that in newborns and children in the first year of life, PURA syndrome is manifested by a development disorder of the nervous system that proves itself as feeding difficulties in combination with respiratory failure and severe hypotension at birth, which is the cause of respiratory disorders, including apnea and hypoventilation (NEDRIHF). Many newborns require mechanical ventilation and tube feeding. Patients have a general development delay, often without progressing the capacity to walk or talk, although the severity of the disease varies. Brain imaging often shows hypomyelination and parenchymal atrophy.

Recurrent epileptic seizures are also common in PURA syndrome. Attacks usually begin before the age of 5 with uncontrollable muscle twitches. Generalized tonic-clonic convulsions may also develop and are accompanied by loss of consciousness and muscle rigidity. In people with PURA syndrome, seizures are often difficult to control. Other peculiarities in people with PURA syndrome may include abnormalities of the heart, eyes, urogenital tract, gastrointestinal tract, and skeleton system [4][5].

The aim of the study was to diagnose PURA syndrome in a newborn.

Description of the clinical case

The child, Nazar S., entered the Rostov Research Institute of Obstetrics and Pediatrics (RRIOP) of the Federal State Budgetary Educational Institution of Higher Education of the Rostov State Medical University of the Ministry of Health of Russia (Director – MD A.A. Lebedenko) in the Department of Pathology of Newborns and Premature Babies of the RRIOP (Head of the Department – PhD K.I. Lazareva) at the age of 4 days of life for examination and treatment from the maternity hospital.

The child was born to a 29-year-old mother suffering from chronic pyelonephritis (remission), mild myopia OU, complex myopic astigmatism OU, and chronic cystitis (remission stage). The mother had grade 1 mitral valve prolapse. The child was born from the second pregnancy. The first one was completed with childbirth in 2008 and proceeded without peculiarities; the child was healthy.

This pregnancy proceeded with trichomoniasis at 12 weeks, candidal colpitis at 23 weeks, and moderate anemia at 30 weeks. The first movements of the fetus, according to the mother, were noted from 20 weeks.

The second birth proceeded through the natural birth canal in a cephalic presentation at the gestation term of 39 weeks and 1 day. Pre-delivery discharge of amniotic fluid was noted. The main parameters of the newborn were as follows: weight 2800 g, length 50 cm, head circumference 32 cm, chest circumference 31 cm, and Apgar score 8–9 points. The child was born in a satisfactory condition. From the 3rd day of life, subicteric skin was noted.

In the children's department of the maternity hospital, the child's condition was regarded as moderate, stipulated by the manifestation of neurological symptoms on the 2nd life day in the form of muscle hypotension, a positive Babinski reflex on both sides, a decrease in the physiological reflexes of the newborn (crawling, walking, support), a symptom of "short neck" and "tightened shoulders", and left-sided torticollis. Periodically large-scale tremor of the upper and lower extremities was noted. On the 4th life day, an increase in neurological symptoms drew attention; among them was the emergence of oculomotor disorders represented by floating movements of the eyeballs, horizontal nystagmus, Graefe's symptom, and the "setting sun" symptom; as well as increased tremor of the limbs and chin and convulsive readiness. Pulse oximetry revealed that the indicators were within the normal range (HR – 132–136 per 1 minute; SpO₂ 98–99%).

The child was on a medical-protective regime, fed through the horn with expressed breast milk of 35.0 ml every 3.5 hours, which he sucked sluggishly, slowly, and did not burp. The child was examined by the resuscitator on duty to decide on further tactics for managing the child; according to the severity condition and an increase in neurological symptoms, the child was transferred to the department of pathology of newborns and premature babies.

The child was admitted to the department on the 4th day of life. Upon admission, the general condition of the child was regarded as severe stipulated by pronounced signs of neurological symptoms. He was transferred to tube feeding. The examination revealed the following features: pale pink skin covers, subicteric face and upper shoulder girdle, and perioral acrocyanosis at rest decreasing with the supply of humidified oxygen. In addition, the following signs were found: the light sclera, physiological engorgement of the mammary glands, and the absence of edema and pastiness. Moreover, soft tissue turgor was a little reduced; the subcutaneous fat was thinned; the muscular system was poorly developed. At admission, body weight was 2565 g, body length was 50 cm, head circumference was 32 cm, and chest circumference was 31 cm. The weight deficit was 28%. Lymph nodes were not enlarged and painless on palpation. The shape of the skull corresponded to plagiocephaly on both sides; a large fontanel 2.0 × 2.0 cm was revealed at the level of the skull bones. The small fontanel was slit-like. The chest was cylindrical; the limbs were not deformed. Respiratory rate corresponded to 38 in 1 minute and was rhythmic. The percussion-pulmonary sound was heard over the entire surface of the lungs. Breathing proceeded without the participation of auxiliary muscles. During auscultation, physiologically weakened breathing was heard in both lungs but wheezing was not heard. The heart rate was 144 beats per minute; the pulse was characterized by satisfactory tension and filling. The apex beat was in the 4th intercostal space. Heart sounds were rhythmic and muffled with a gentle systolic murmur at the apex. The abdomen was soft, painless on palpation, with hypotension of the muscles of the anterior abdominal wall. The state of the umbilical wound was in the Rogovin bracket. The liver protruded 1 cm from under the edge of the costal arch; the edge was elastic. The spleen was not enlarged. The stool on examination was yellow-green, mushy. Urination was free. The genitourinary system was formed according to the male type; the testicles were in the scrotum.

Neurological status corresponded to the following characteristics: the child was conscious but lethargic with the symptom complex of a "sluggish" child. The reaction on examination was reduced; in case of painful irritation, the child responded with a loud short-term cry. The pupil diameter was normal, D=S, and the reaction to light was "live". The movements of the eyeballs were floating with horizontal nystagmus. The child did non manifest any meningeal signs. Physiological reflexes of oral-spinal automatisms were sharply reduced; sucking and swallowing reflexes were sluggish; abdominal reflexes were reduced. The motor sphere corresponded to the following characteristics: the "frog pose" was manifested; the volume of active movements was sharply reduced; resistance to passive movements in the limbs was reduced. Tendon reflexes in the lower extremities were with the expansion of reflexogenic zones, in the upper extremities they were reduced, D=S. Stop myoclonus was manifested. Muscle tone was characterized by pronounced hypotension in the proximal distal parts of limbs; and "calcaneal feet" were revealed. With traction by the hands, general hypotension was found. Reflexes of support and step automatism were depressed; at axillary hanging, pronounced leg extensions were marked. Finely, sweeping tremor, spontaneous and contact shudders of the upper and lower extremities were manifested. During sleeping, frequent swallowing movements and elements of chewing and "smacking" were noted. In addition, twitching mimic muscles and eyelids (opercular convulsions) were revealed, as well as left torticollis and "stretched" neck.

The child was in the department for 33 days, from January 24, 2021 to February 26, 2022. During the hospitalization, all the necessary laboratory and instrumental diagnostics were carried out that allowed making the main and concomitant diagnoses to determine the tactics of management and treatment of this child. At the admission of the child on the 4th day of his life, in the general blood test, leukopenia (6.8×10⁹/l), neutropenia (29%), and thrombocytopenia (143×10⁹/l) were revealed, and in the general urinalysis, pathology was not found. On the 5th day of life, short-term apnea emerged. In addition, hemorrhagic syndrome was found in the form of intestinal bleeding, which required the introduction of single-group and single-Rhesus fresh frozen plasma in order to correct the plasma coagulation link of hemostasis. When monitoring the acid-base state of the blood, metabolic acidosis and hyperlactatemia (2.8 mmol/l) were noted.

In the general blood test, thrombocytopenia remained (112×10⁹/l) but in the blood formula, a shift to stab neutrophils (5%) was revealed. A biochemical blood test showed hyperbilirubinemia (171 µmol/l) related to the indirect fraction (149 µmol/l), hypoproteinemia (42.3 g/l), hypoalbuminemia (31.4 g/l), and normal levels of transaminases (AST and ALT). The investigation of the coagulogram did not reveal a decrease in the synthesis of blood coagulation factors. It was noteworthy that over the disease course, in the biochemical analysis of the blood, against the background of a decrease in total bilirubin (171 µmol/l → 85.3 µmol/l), its direct fraction increased, the percentage of which from total bilirubin amounted to 12.9%→19.2%→27%. Meanwhile, the AST level increased by 4 times (from 22.4 U/l to 90.7 U/l) on the 13th life day. The value of creatine phosphokinase on the 6th life day was standard (59 U/l), however, in the dynamics of the examination on the 13th day of life, it increased by 3 times (187 U/l). The GGT value was increased and amounted to 391.7 U/l.

A blood test for hormones revealed a decrease in the levels of thyroid-stimulating hormone to 0.43 μIU/ml and triiodothyronine to 1.1 Pg/ml; a decrease in the cortisol level (11 nmol/l) simultaneously with an increase in the level of adrenocorticotropic hormone (92.7 pg/ml).

In the laboratory of molecular pathology "Genomed", Moscow, tandem mass spectrometry analysis of biomaterial was performed at the age of 16 life days. It detected an increase in glycine concentration up to 1613.217 μM/l, which was fixed for non-ketotic hyperglycinemia.

The child underwent the following instrumental examinations.

The neurosonogram showed that the lateral ventricles were slit-like and corresponded to 1.0×1.0 mm, the 3rd ventricle was 4.0 mm, and the cavity of the pellucid septum was 6.7 mm. An increase in diffuse echogenicity of the periventricular region, the region of the subcortical nuclei and the thalamus was revealed. In addition, heterogeneity of the vascular plexuses was marked. There were found pronounced signs of immaturity of the brain as well as diffuse hypoxic-ischemic changes in the brain parenchyma and swelling of the periventricular zones. Moderate dilatation of the third ventricle was observed. On the left, in the region of the anterior horn of the lateral ventricle, a subependymal compaction (2.0×5.4 mm) was located; it was at the lysis stage.

Transcranial dopplerography showed severe cerebral arteriovenous insufficiency, attesting to transient intracranial hypertension with hemolytic-dynamic disorders by indirect signs.

Magnetic resonance imaging (MRI) of the brain revealed no malformations. The MRI image showed a small cyst of the pellucid septum, slight dilatation of liquor-containing spaces, and ischemic injury of the corticospinal tracts of the brain. MRI signs of pathology of intracranial arteries and veins were not determined.

An ultrasound examination of the abdominal organs revealed a mild dilatation of the pelvicalyceal complex of both kidneys. The size of the adrenal glands was within the age norm. Echocardioscopy found functioning fetal ducts (open oval window), while the contractility of the left ventricle was preserved.

The electroencephalogram (EEG) recorded moderate cerebral changes including decreased functional lability of cortical processes and strengthening of the ascending activating influences of the reticular formation of the brain stem. Typical epicomplexes and paroxysmal activity were not registered.

An X-ray of the chest and abdominal organs revealed a bilateral decrease in the pneumatization of the lung tissue and hyperpneumatization of intestinal loops.

Highly specialized doctor consultations were also held. The endocrinologist revealed a low level of cortisol (11 nmol/l) and an increase in adrenocorticotropic hormone (92.7 pg/ml) in the blood, which is regarded as transient hypocorticism. The ophthalmologist found retinal angiopathy of the first degree in both eyes. The pediatric neurologist revealed a consequence of a cerebrospinal birth injury against the background of intrauterine hypoxia and cerebral ischemia. In addition, periventricular hemorrhage of the 1st degree on the left, syndrome of hemoliquorodynamic disorders, symptomatic epilepsy, and muscular dystonia syndrome were found. Taking into consideration convulsive syndrome and myoclonic seizures, it was necessary to exclude hereditary metabolic diseases. The geneticist confirmed the normal karyotype, 46 XY.

On the basis of clinical, laboratory, and instrumental data, the child was given the main clinical diagnosis "P05.2 Malnutrition of the fetus without mention of "low weight" or “small” for gestational age, as a child was born at a gestational age of 39 weeks and 1 day with a birth weight of 2800 g, corresponding to the gestational age. P52.0 Intraventricular non-traumatic hemorrhage in a newborn of I degree on the left. Cerebral ischemia of moderate severity, acute period, CNS depression syndrome, syndrome of paroxysmal conditions, syndrome of pseudobulbar disorders, syndrome of vegetative-visceral dysfunction, installation left-sided torticollis”.

Concomitant clinical diagnoses were made: "E72.5 Hereditary genetic metabolic disease: nonketotic hyperglycinemia?; Mitochondrial disease, unspecified?; Transient hypocorticism. P39.8 Infection specific for the perinatal period of unspecified viral/bacterial etiology (Staphylococcus aureus, Streptococcus agalactiae) with the development of perinatal CNS injury, hemorrhagic syndrome, mild anemia, and transient thrombocytopenia. Q21.1 Functioning fetal communication: open foramen ovale".

The child underwent the following therapeutic measures:

• infusion therapy by using 10% glucose with components, 10% aminoven-infant, 20% lipofundin;
• antihemorrhagic therapy with vikasol and 12.5% etamzilat;
• antibacterial therapy with sultasin, cefotaxime, and amikacin;
• in order to prevent apnea, therapy with 20% caffeine-benzoate;
• metabolic therapy with cytoflavin, ascorbic acid, and 30% elkar;
• nootropic therapy with cortexin;
• vitamin therapy with pyridoxine alternated with thiamine chloride;
• correction of hemostasis with fresh frozen plasma B(III) Rh (+) No. 1;
• biological preparations, namely, buckset baby;
• hepatoprotective therapy with ursofalk;
• selective decontamination with coliproteic bacteriophage;
• prevention of osteopenia with aquadetrim;
• interferon therapy with Genferon-Light suppositories;
• hormone therapy with Cortef;
• oxygen therapy;
• orthopedic Shants collar.

Against the background of the therapy during the child’s stay in the hospital (33 days), the boy's appetite improved, and positive dynamics in body weight (gained 893 g) were noted. In the time of passive movements, there was muscle resistance in the limbs, while active movements were in full. The pupil diameter was normal, S=D; the reaction to light was preserved. He briefly tried to follow the toy, and briefly tried to fix his gaze. The floating movements of the eyeballs were preserved, however, they were less pronounced in dynamics. Convulsions and convulsive readiness were not marked. Tendon reflexes were brisk from the lower and upper extremities, D=S. Muscle tone was dystonic with a tendency to hypotension of the muscles of the upper and lower extremities, "calcaneal" feet were also marked. With traction by the hands, the grasping reflex was more pronounced, the child tried to pull itself up for a short time. Full abduction of thighs was manifested. Physiological reflexes of oral-spinal automatisms were reduced, abdominal reflexes were evoked; swallowing reflex and the sucking reflex were restored. Reaction to a painful stimulus came out in screaming. The child woke up before feedings, the time of wakefulness between feedings increased. There was no regurgitation, no vomiting. Enteral feeding with expressed breast milk was conducted every 3 hours with 90 ml milk; sucking was active. During feedings, choking was noted 1–2 times per day.

The child was discharged in a satisfactory condition under the local pediatrician’s supervision with recommendations, at the residence place.

A reinvestigation by tandem mass spectrometry in the laboratory of molecular pathology was carried out at the age of 2 months of life and the results attested to no hereditary aminoacidopathy, no organic aciduria, and no defects in mitochondrial beta-oxidation.

During the first year of life, the child had a delay in psychomotor development. The child was hospitalized twice in children's departments for rehabilitation treatment. At the age of 5 months, the child was hospitalized owing to latent cytomegalovirus infection and right-sided upper lobe pneumonia. At the age of 10 months, physical development was disharmonious due to excess weight. Body weight was 11 kg (percentile 90–97%). The body mass index amounted to 19.04. Height was 76 cm (percentile 75–90%). Pathology of hearing and vision were not revealed. Cerebral and meningeal symptoms in the neurological status were not revealed. The child fixed the gaze and followed the objects. Sucking and swallowing were normal. The tongue in the oral cavity was a little dystonic. Muscle tone in the extremities was hypotonic. Tendon reflexes were triggered but reduced. Pathological reflexes were not revealed. He held his head since 7 months, rolled over from his back to his stomach since 9 months, in speech there was a paucity of sound reserve, mostly cooing. The child examined his hands, held nested toys. Psychomotor development corresponded to 4–4.5 months.

On the EEG, the cortical rhythm was formed. Epileptiform and focal pathological activities were not registered.

On the electromyogram, there was a decrease in the amplitudes of M-responses, as well as a decrease in the amplitudes and duration of the motor unit potentials (MUP), an acceleration of the recruitment of the MUP; while the indicators of the turn-amplitude analysis were below the normative limits. The main clinical diagnosis was made to the child: "G71.1 Myotonic syndrome in a child with syndromic pathology. Delayed psychomotor development". Concomitant clinical diagnosis corresponded to "K26.8 Disorder of self-verticalization, sitting. Z99.8 Dependence on a wheelchair, seating support, standing support".

In order to search for genetic variants as a probable cause of the disease, whole genome sequencing of the child's DNA was carried out at the "Evogen" Medical Genetic Laboratory (Moscow). Demand for this investigation arose from a complexity of indications, including data of anamnesis preserved at the age of 1 year 5 months; severe delay in psychomotor development; lack of a positive effect from ongoing courses of rehabilitation therapy; as well as the absence of identified abnormalities in the results of broad metabolic screening for amino acids, copper, ceruloplasmin, uric organic acids, and mucopolysaccharides.

A search for pathogenic mutations associated with a clinical diagnosis and other hereditary diseases having similar phenotypic manifestations was carried out, and its results allowed geneticists to make the following conclusion.

A heterozygous variant, which has previously not been described in the literature, was found in the exon 1 of the 1 PURA gene, related to a reading frame shift of p.Thr101LeufsTer124. Pathogenic variants in the PURA gene induce the development of an autosomal dominant neurodevelopmental disorder with neonatal respiratory failure, hypotension, and feeding difficulties (OMIM 616158).

The variant was not found in the population frequency database gnomAD v.3.1.10., and with a high probability brings about the loss of function of the corresponding gene copy. No other significant changes matching the search criteria were found.

Discussion

The particular characteristics of this case were stipulated by the difficulty of early detection of this rare disease, namely PURA syndrome, which is related to hereditary neuromuscular diseases accompanied by diffuse muscle hypotension. More than 80 different diseases have been described, which go along with a similar symptom complex at an early age. To designate diffuse muscular hypotension regardless of its origin, the term "sluggish child" is used but it does not have nosological independence [6].

In the described clinical case, the algorithm of differential diagnostics began precisely with the discovery of the "sluggish child" symptom complex in the child. Considering that the causes of diffuse muscular hypotension can be associated with hereditary metabolic diseases, as well as with perinatal hypoxic-ischemic and traumatic lesions of the nervous system, the differential diagnosis was carried through the choice between intraventricular non-traumatic hemorrhage in a newborn of the 1st degree on the left, cerebral ischemia of moderate severity, and hereditary genetic metabolic disease. The latter was excluded. Only at the age of 1 year and 5 months, the child underwent whole genome DNA sequencing, which resulted in the detection of a mutation in the PURA gene with the following diagnosis "PURA Syndrome". This case demonstrates that, due to the extensive clinical heterogeneity of PURA syndrome, the diagnostic process can be very challenging, even for experienced clinicians.

The difficulties of diagnosing hereditary neuromuscular diseases in newborns are associated with the non-specificity of symptoms, their camouflaging to other diseases including epilepsy, neuroinfection, perinatal pathology, and the low incidence of this pathology.

Conclusion

Thus, in the diagnostic search, it must be considered that hereditary diseases accompanied by muscular hypotension affect disorders at the gene or chromosomal level. Despite the fact that PURA syndrome is a rare genetic disease, the clinical symptoms of which are non-specific, it is important to remember that this syndrome has common features corresponding to congenital myasthenic syndrome. Neonatologists should be wary of this pathology and have the opportunity to get results of whole genome DNA sequencing when the child is timely referred to a geneticist’s consultation. Early diagnosis of the PURA syndrome is necessary to determine the scope of complex therapeutic effects, predict the disease course, and prevent the recurrence of childbirth with this pathology.