Anomalies (or malformations) of the brain (malus (Latin) is unfit, bad, evil; phorme (Greek) is form) are irreversible structural defects, which result from impairments of normal pre- or postnatal development. The types of anomalies are determined by the time term and duration of the pathological impact. Probable causes of anomalies are often related to genetic defects, intrauterine infections such as toxoplasmosis, syphilis, rubella, cytomegalovirus, herpes simplex virus, and HIV, drug impact on the fetus, maternal illnesses during pregnancy including diabetes and other metabolic disorders, X-ray exposure at the early stages of pregnancy, alcohol abuse, etc. Besides, an unfavorable course of pregnancy or childbirth, as well as insufficient oxygen supply to the structures of the brain and spinal cord of the fetus, promote the emergence of disorders at the metabolic and microcirculatory levels.

Hereditary metabolic diseases (HMDs) in pediatric practice are a huge class of monogenic hereditary diseases caused by mutations of genes encoding enzymes and transport or signal proteins. HMDs are currently among the leading problems in the clinic, numbering more than 500 nosological forms, and their number is constantly growing. Their early diagnosis gives a doctor an opportunity to apply effective treatment methods, which are ineffective or unsuccessful at later stages of the pathological process. In addition, a correct final diagnosis is necessary for conducting competent medical and genetic counseling of the family. One of the groups of HMDs is presented by peroxisomal diseases, which emerge as a result of dysfunction of peroxisomes (tiny vesicles containing a set of enzymes on the membrane surfaces) [1–2].

According to modern classification, they are divided into 3 large groups1 [1]:

Treatment options for patients with peroxisome biogenesis disorders are limited since severe abnormalities develop in utero and specific therapy in early life terms is currently lacking.

The purpose of this study is to highlight the problems, which a practicing pediatrician faces upon attempting early diagnostics of peroxisomal diseases in the neonatal period. Unfortunately, in Russian practical medicine, prenatal and early natal diagnosis of peroxisomal diseases is currently difficult.

The boy was born on December 16, 2021, in the maternity department of the Regional Clinical Hospital (RCH No. 2), from a 32-year-old mother, who worked as an X-ray laboratory technician, with 0 (I) Rh (+) blood type, and an extremely burdened somatic, infectious, and gynecological history, which included stage 2 obesity, arterial hypertension (140/80 mm Hg, taking dopegit), varicose veins of the lower extremities, angiopathy of the retinal vessels OI, chronic herpesvirus infection, uterine fibroids, polycystic ovary disease, infertility, and menstrual irregularities.

That was Pregnancy I, and was accompanied by numerous complications and disorders:

The birth was first, urgent (at 39.4 weeks of gestation); primary weakness of labor was evident, there was no effect on oxytocin infusion, and surgical delivery was required. The baby was delivered on December 16, 2021 at 19:00, weight was 3000 g, length was 50 cm, head circumference was 36 cm, chest circumference was 33 cm, and the Apgar score was 7–8 points.

At birth, the child’s general condition was assessed as satisfactory but there was no cry. Moreover, dysembryogenesis stigmas in the form of a hydrocephalic head shape, deformation of the auricles, increased mobility in the joints, and muscle hypotonia were recorded. The supply of humidified oxygen was established and the child was subsequently transferred to the intensive care unit (ICU). The child was lethargic and sucked poorly through a nipple.

On the second day of life, after stabilizing the child’s condition, he was placed in the department with his mother, and it was recommended to feed him with formula from a bottle, but the child sucked very sluggishly. On the third day of life, in his mother’s arms, the child’s skin color changed to purple-cyanotic, and tonic tension of the limbs appeared, which was followed by clonic twitching. Owing to the deterioration of the general condition and the appearance of neurological symptoms such as lethargy, hypodynamia, sluggish sucking reflex, and a short-term attack of clonic-tonic convulsions in the limbs relieved by inhalation of humidified O2, the child was again transferred to the ICU. Here, respiratory therapy with humidified oxygen through a mask was continued, a peripheral catheter was installed; later, a subclavian venous catheter was fixed on the right, infusion therapy was performed, the child was fed through a tube and a bottle. In dynamics, the child’s condition remained moderate with persistent central nervous system (CNS) depression, lethargy, hypodynamia, hyporeflexia, muscle hypotonia, suppression of the sucking reflex, and the presence of crepitant wheezing in the right lung. No convulsions were noted.

Results of the examination in the ICU in Regional Clinical Hospital No. 2:

Until January 12, 2022, the child was under the conditions of the ICU of RCH No. 2 for 26 days, where he received the following treatment: intravenous drip and intravenous jet stream by 10% glucose with other components; antibacterial therapy with sultasin 75 mg/kg from December 20, 2021, protosidine 80 mg/kg/day and amikacin 15–10 mg/kg/day from December 29, 2021; as well as cytoflavin, vitamins B1, B6, actovegin; intramuscular introduction of 1% vikasol, oral administration of depakine syrup at dose 30–20 mg/kg/day, gliatilin, diacarb, bifidumbacterin. Besides, there were respiratory support O2 through a mask, phototherapy, enterally expressed breast milk/Pre Nan formula 55–60 ml 7 times a day through a tube.

On January 12, 2022, the child was transferred to the Department of Pathology of Newborns of the Research Institute of Obstetrics and Pediatrics (DPN of RIOP) with the clinical diagnosis “Main: P91.0 Degree 3 cerebral ischemia, degree 2 intraventricular hemorrhage, CNS depression syndrome, convulsive syndrome, hypertensive-hydrocephalic syndrome”. The concomitant diagnosis was “Intrauterine infection of unspecified etiology. Right-sided pneumonia, Respiratory failure (RF 1). Neonatal jaundice. HMD?”

The results of the histological examination of the placenta from December 31, 2021 and January 24, 2022 were as follows: the 3rd trimester placenta was characterized by the presence of intermediate villi; immature, terminal villi were congested with stromal edema and perivascular and perivillary hemorrhages. Compensatory angiomatosis of the villi was weakly expressed. The formation of a small number of syncytiocapillary buds, obliterating angiopathy of the supporting villi and intermediate villi, and focal hemorrhages in the basal plate and intervillous space were noted. In addition, occasionally afunctional zones and areas of intervillous hemorrhages, as well as a large amount of viral DNA inclusions were revealed. Single lymphoid cells were noted in the umbilical cord and membranes.

The child was admitted to the DPN of RIOP at the age of 27 days. The body weight on admission was 3210 g, body length was 53 cm, head circumference was 38 cm, chest circumference was 31 cm, temperature was 36.7 °C, HR was 148–184 beats per minute, RR was 44 in/out breath per minute, and SatO2 was 93%. The general condition on admission was severe, due to signs of neurological symptoms, CNS depression, clonic-tonic convulsions, and moderate signs of respiratory failure. The results of the comprehensive examination in the institution are presented in Tables 1–10.

During a general clinical and laboratory examination of the newborn (Tables 1–6), a tendency towards anemia, moderate leukocytosis, eosinophilia, neutrophilia, and hypoproteinemia was revealed.

Thus, a comprehensive bacteriological, virological, and immunological examination (Tables 7–10) of the newborn revealed the presence of an intrauterine infection of unspecified viral-Klebsiella etiology with the development of right-sided pneumonia, mild anemia, and perinatal CNS injury. To clarify the diagnosis, further consultations with specialist doctors and instrumental examinations were carried out:

The dynamics of clinical and laboratory characteristics, the identified markers of herpesvirus infection, the results of the immunological examination related to the pronounced increase in the level of NK cells, and histological data of the placenta indicated intrauterine antigenic stimulation of DNA viral etiology and the need for specific therapy.

Further examination of the child confirmed a severe congenital defect of the CNS, namely congenital malformation of the brain; microgyria, subcortical leukomalacia, lack of differentiation of gray and white matter, cysts of the septum pellucidum and intermediate velum, retrocerebellar cyst, hypoplasia of the corpus callosum, hypoplasia of the transverse and sigmoid sinuses on the left, against the background of perinatal hypoxic-ischemic-hemorrhagic injuries of the brain.

Complex treatment accomplished at the Department of Neonatal Pathology of the Research Institute of Obstetrics and Pediatrics:

Based on the anamnesis, clinical symptoms, and results of laboratory and instrumental studies, the child was given a clinical diagnosis.

Two major competing clinical diagnoses

Associated clinical diagnoses:

Dynamics of the disease progression

Against the background of the complex therapy, certain stabilization in the somatic status was noted: the child gained weight, inflammatory changes in the lungs were relieved, soft tissue turgor improved, dry skin was absent; however, the convulsive syndrome persisted for a long time in the form of polymorphic paroxysms, myoclonus of the eyelids, gaze spasms, vertical and horizontal nystagmus, opercular convulsions, torso rotation (mainly to the left), turning of the arms inward with the hands clenched into fists, with turning of the head to the side, with opercular convulsions with tonic tension of the limbs and subsequent generalized clonic convulsions and myoclonus of the upper limbs, clonic rhythmic propulsive “folding”, clonus of the feet (more in terms of the right one), with general cyanosis, short-term apnea, and a drop in saturation levels to 60%, resolving on their own or after administration of humidified oxygen. The convulsions occurred in series for approximately 1–2 minutes and persisted 1–3 times a day but not every day (2–3 times a week). Such extensive convulsions arose spontaneously, in response to touch.

The child had no reaction to surrounding stimuli, in particular, he did not react to sounds, did not follow the object, did not fix his gaze, and the symptom complex of a “lethargic child” persisted. The child’s amimic face, wide bridge of the nose, smoothed nasolabial folds, slightly open mouth during sleep and wakefulness, absent (rare) blinking, including to a visual stimulus (during deep sleep the eyelids close), and hyperextension of the phalanges of the fingers (“clawed paw”) were noteworthy.

On February 7, 2022, after consultation via the telemedicine technology center with the Federal State Budgetary Educational Institution of Higher Education “Saint Petersburg State Pediatric Medical University” of the Ministry of Health of the Russian Federation, it was recommended to conduct an additional examination including detecting blood ammonia and to hospitalize the child in the Department of Pathology of Newborns and Early Infancy of the Perinatal Center of this institution from February 13, 22. At the age of 1 month 28 days, the child was transferred in a serious condition due to the underlying disease (t°=36.6 °C, HR = 152 bpm, RR = 38 per min, SatO2 = 94–99%, BP – 76/33 mm Hg, weight – 4400 g, height – 57 cm). In this department, the child’s condition remained serious and stable throughout the entire follow-up period. He was nursed in the ICU, in a crib. The child did not need respiratory support, he was sufficiently oxygenated, no episodes of apnea or desaturation were noted; his blood acid-base balance was compensated. He received full enteral nutrition with the Similac Gold mixture through a tube, he absorbed it and gained weight. No convulsive activity was observed during the observation period.

Inflammatory changes were detected in the blood, namely leukocytosis at the level of 17.5–15.7x109/l and neutrophilia at the level of 45–39%, but the CRP level remained normal. Bacterial cultures in the sputum, pharynx, and stomach revealed Klebsiella pneumoniae, sensitive only to polymyxin B. NSG revealed US signs of giant subependymal cysts on both sides with uneven contours of the soft membranes. MRI of the brain revealed a picture of diffuse changes in the white matter of the cerebral hemispheres, moderate external hydrocephalus, hypoplasia of the corpus callosum, cyst of the intermediate velum, and cyst of the septum pellucidum. The chest X-ray showed uneven pneumatization on the right, an unclear pulmonary pattern due to the vascular component and foci of infiltration, and an extension of the mediastinum in the upper section due to the thymus gland.

Consultations with medical specialists:

The main diagnosis was “Q04.3 Encephalomyelopathy (possibly in the structure of HMD related to peroxisomal diseases); Muscle hypotonia syndrome; Paresis of the right foot; Bulbar dysfunctions; Partial ptosis of the upper eyelid on the left”. The concomitant diagnoses were “P90 Epilepsy (metabolic) focal with evolution to generalized seizures”; “H90.6 Right sensorineural hearing loss of degrees III-IV”; “Primary hypocorticism”; and “Intrauterine infections, Klebsiella etiology, with the development of right-sided pneumonia”.

The boy stayed at the Department of Pathology of Newborns and Early Infancy of the Perinatal Center of Saint Petersburg State Pediatric Medical University for 12 days, receiving complex therapy. He was discharged with recommendations.

Unfortunately, in this clinical case, the relatively early diagnosis of peroxisomal pathology did not enable a quick full clinical diagnosis and specific therapy for the child that worsened the disease prognosis.

1. Nervous system in peroxisomal diseases. https://meduniver.com/Medical/Neurology/nervnaia_sistema_i_peroksisomnie_bolezni.html