A case of congenital malformation of the brain in a newborn on the background of hereditary metabolic disorders

Introduction

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]:

1. An impairment of peroxisome biogenesis, their complete absence, or disturbances in their functional activity are related to Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease, punctate chondrodysplasia of the hip joint, and syndrome similar to Zellweger syndrome.
2. A deficiency of one peroxisomal enzyme determining defects in beta-oxidation is associated with pseudoadrenoleukodystrophy of newborns, X-linked adrenoleukodystrophy, pseudo-Zellweger syndrome, and bifunctional enzyme deficiency.
3. A deficiency of one peroxisomal enzyme without beta-oxidation defects is related to Refsum disease, pseudochondrodysplasia of the hip joint, di-(tri-)hydrocholestane acidemia, and mevalonic aciduria.

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.

Full description of the clinical case

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:

• in the first trimester, the patient had a threat of spontaneous abortion (bloody discharge, outpatient treatment); taking aspirin from the 12th week; anemia; colpitis from 12–13 weeks; gestational hypothyroidism with medication compensation;
• in the second trimester, there were acute respiratory viral infections without an increase in body temperature at 16–18 weeks of pregnancy; colpitis at 22–23 weeks; taking aspirin due to risk of preeclampsia; COVID with an increase in body temperature for 5 days up to 37.3 °C, nasal congestion, and loss of smell at 23 weeks with symptomatic therapy;
• in the third trimester, the patient had arterial hypertension (taking dopegit); chronic herpesvirus infection without exacerbation; detection of umbilical cord entanglement around the fetus’s neck and an increase in the size of the fetus’s head at 36 weeks of pregnancy revealed by ultrasound (US) data; inpatient treatment due to the high risk of preeclampsia and signs of fetal hypoxia according to transcranial dopplerography at 38 weeks of pregnancy.

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:

1. A complete blood count revealed no pathological changes.
2. The biochemical blood test from December 22 to January 7, 2021 was specified by the following indicators: blood glucose was 3.8–4.2 mmol/l, total bilirubin was 200.6–24.1 μmol/l, direct bilirubin was 5.0–4.4 μmol/l, total protein was 56.5–48.9 g/l, albumin was 37.2–29.3 g/l, urea was 2.9–2.2 mmol/l, and C-reactive protein (CRP) from December 22, 2021 was 10 mg/l.
3. Neurosonography (NSG) on December 20, 2021, December 23, 2021, and January 10, 2022 revealed a heterogeneous multi-chamber formation of 10.6 × 25 mm with signs of lysis in the left lateral ventricle (LV) and a similar formation 11.5 × 21.3 mm in the right LV; peripheral venous catheter of the 2nd degree on both sides and moderate dilation of the LV.
4. Chest X-ray examinations on December 19, 2021 and January 7, 2022 found a pronounced increase in the pulmonary pattern in the root zones on both sides without infiltrative changes.
5. Consultations with a neurologist on December 22, 2021 and January 10, 2022 resulted in revealing cerebral ischemia degree 2–3, depression syndrome, and convulsive syndrome.
6. A geneticist’s consultation on December 21, 2021 detected skin hyperextensibility and hypermobility.
7. Consultation with a neurosurgeon at the Regional Children’s Hospital on December 30, 2021 detected intrauterine infections and convulsive syndrome. The child did not require neurosurgical treatment.

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:

1. The conclusion based on the results of medical genetic testing obtained from the Genomed laboratory of molecular pathology, Moscow, attested that no hereditary aminoacidopathies, organic acidurias, or defects in mitochondrial beta-oxidation were found upon blood investigation using the TMS method (dated January 5, 2022).
2. The conclusion based on the results of a medical genetic study received from the Genomed laboratory of molecular pathology, Moscow, was the following: to identify spinal muscular atrophy, search for deletions of exons 7–8 of the SMN1 gene was accomplished at January 5, 2022 and 2 copies of the SMN1 gene were detected.
3. The conclusion based on the results of medical genetic testing from the selective screening laboratory of N.P. Bochkov Research Center for Medical Genetics, Moscow, No. 053755293 from February 8, 22, was the following: the concentration of acids and the ratio of acid concentrations were increased in the blood plasma. The concentration of phytanic acid was 0.01 mg/ml (the norm is 0–3.11 mg/ml); the concentration of pristanic acid was 1.12 μM/l (the norm is 0.57–0.86 μM/l). These changes were characteristic of peroxisomal pathology. It was recommended to conduct DNA diagnostics and provide magnetic resonance imaging (MRI) to compare clinical and laboratory data.
4. The cytogenetic study (karyotype), accomplished in the medical genetic laboratory of the Federal State Budgetary Educational Institution of Higher Education Rostov State Medical University, dated January 17, 2022: 46XY, revealed a normal male karyotype.
5. The bacteriological analysis of the nasal mucosa from January 13–20, January 31, 2022 found Klebsiellae pneumonia in a number of 10⁷–10⁴–10⁶.
6. The bacteriological analysis of the pharyngeal mucosa from January 13–20, January 31, 2022 revealed Klebsiellae pneumonia in a number of 10⁷–10⁶.
7. The bacteriological analysis of discharge from the eyes from January 13, 2022 did not detect anaerobic microflora and Candida
8. The bacteriological blood test from January 13, 2022 and February 5, 2022 showed that aerobic, anaerobic microflora, and yeast fungi of the genus Candida were not isolated during the investigation.
9. The native material (feces) did not contain pathogenic enterobacteria upon testing from January 13, 20
10. The immunogram from January 21, 2022 had the following indicators: T-lymphocytes 58.4%; T-helpers 46.8%, T-cytotoxic 17.1%, NK cells 20.0%, B-lymphocytes 15.3%; IgG 12.52; IgA 0.12, IgM 0.32.

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.

11. Neonatal screening from December 20, 2021 was normal.
12. Audio screening from December 19, 2021 showed the following results: on January 17, 2022 R(+/-) L(+/-); on January 27, 2022 R(+/-)L(+/-); and R(-)L(-) on February 10, 2022.
13. The radiograph of the chest organs and abdominal organs in a direct projection from January 13, 2022 revealed no focal or infiltrative changes in the lungs but found X-ray signs of bilateral enhancement of the bronchovascular pattern and hyperpneumatization of intestinal loops.
14. The results of the X-ray of the cervical spine in two projections from January 12, 2022 was the following: the X-ray picture of instability of the atlantoaxial joint; Retrospondylolisthesis C3 of the 1st degree, and C4 of the 1st degree.
15. Echocardiography of the heart on January 12, 2022 revealed patent foramen ovale (PFO); abnormal chord in the cavity of the left ventricle (LV); LV myocardial contractility was preserved.
16. The US examination of internal organs, kidneys, and adrenal glands from January 12, 2022 showed minor changes in the liver parenchyma, dilation of the renal pelvicalyceal system (mainly on the right), and slight enlargement of the right adrenal gland.
17. Electrocardiography (ECG) from January 13 and February 8, 2022 revealed sinus rhythm, tachyarrhythmia 160–190 beats/min, incomplete block of the posterior branch of the left bundle branch and right bundle branch of His, and ECG signs of right ventricular myocardial hypertrophy.
18. NSG from January 12 and 19, 2022 showed the following results: S:D=7.2:6.2 mm, III ventricle – 1.8 mm, V.Gall – 0.14 m/s.; periventricular edema of increased echo density was diffuse; a multi-chamber subependymal pseudocyst was located on the right – 25.0×11.2 mm and on the left – 23.0×10.7 mm, periventricular hemorrhage – 6.7×7.0 mm.; hematoma in the lysis stage on the right — 23×10.9 mm and on the left — 23×8.2 mm; increased venous blood flow; expansion of the anterior horns of the lateral ventricles, bodies of the lateral ventricle.
19. Electroencephalography from January 12, 19, and 28, 2022: upon continuous video monitoring for 1 hour against the background of depakine intake during passive wakefulness and early stages of sleep, against the background of moderately disorganized activity of the delta-theta range with an amplitude of up to 6–7 μV, patterns of stable regional slowing were recorded in the left centro-parietal leads with the inclusion of frequent regional epileptiform complexes of the SSW (sharp-slow wave) type, as well as fragments of local slowing in the right centro-parietal leads with inclusions of polyphasic oscillations, SSW complexes in the right centro-parietal regions (smaller index) during the background recording, 2 attacks were repeatedly recorded, accompanied by a turn of the head and eyes to the right, tonic tension, and clonic twitching of the right upper limb, accompanied by respiratory dysrhythmia.
20. Spiral computed tomography (SCT) of the brain from January 26, 2022 revealed signs of hypoxic-ischemic brain damage, leukodystrophy; cyst of the intermediate velum, slit-like cyst of the septum pellucidum, and retrocerebellar arachnoid cyst. In the projection of the sagittal sinus, multiple calcifications of various shapes and sizes were determined.
21. The SCT scan of the cervical spine from January 26, 2022 found signs of non-closure of the posterior arch of the C1 vertebra and non-closure of the spinous processes. No destructive bone changes in the cervical spine were detected.
22. The SCT scan of the abdominal organs on January 26, 2022 detected signs of hepatomegaly; adrenal glands were not differentiated.
23. MRI of the brain on January 31, 2022 (conclusion of the Head of the Department of Radiation Diagnostics of the Research Institute of Obstetrics and Pediatrics) detected congenital malformation of the brain including abnormalities in the formation of sulci and convolutions, and microgyria; as well as MR signs of periventricular gliotic changes in the white matter, minor dilation of the internal and external cerebrospinal fluid-containing spaces of the brain, thinning of the corpus callosum, cysts of the septum pellucidum, and cysts of the intermediate velum. The MR picture of the white matter of the brain might be differentiated between leukodystrophy and developing leukomalacia. MR signs of pathology of intracranial arteries and veins were not detected.
24. The conclusion of an ophthalmologist after the examination of the fundus on the retinal chamber from January 12 and 29, 2022 detected retinal angiopathy of the 1st degree of both eyes.
25. Consultation with a neurologist on January 13, 2022 identified the following pathologies: early residual organic damage to the CNS of combined genesis (intrauterine viral encephalitis, chronic intrauterine hypoxia, birth cerebrospinal injury), internal hydrocephalus, periventricular leukomalacia, subependymal and retention multilocular cysts, lenticular vasculopathy, hemocerebrospinal fluid dynamics disorder syndrome.
26. Consultation with a neurologist on February 2, 2022 revealed congenital malformation of the brain including 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; as well as atrophic-hydrocephalic syndrome, post-ischemic gliosis of the periventricular zones, epileptic encephalopathy, mixed tetraparesis, and severe psychomotor retardation.
27. A geneticist's consultation on January 13, 2022 revealed the need to clarify the etiology of the disease through a karyotype investigation to exclude chromosomal pathology, analysis of the spectrum of amino acids and acylcarnitines using tandem mass spectrometry, a panel of studies for Zellweiger syndrome and peroxisomal diseases using gas chromatography (mass spectrometry).
28. A geneticist’s consultation on February 10, 2022 stated the following: the clinical picture, convulsions, hypotension, and the test results, namely decreased phytanic acid concentration, suggested a diagnosis of an autosomal recessive type of inheritance from the group of peroxisomal diseases, Zellweger syndrome.
29. Consultations with an endocrinologist on January 14, January 19, and January 26, 2022 led to the following conclusion: taking into account the enlargement of the right adrenal gland in accordance with US data, cortisol monitoring and adrenocorticotropic hormone administration were recommended to prevent hypocorticism; primary hypocorticism was revealed, and hydrocortisone therapy was prescribed. The diagnosis of “Congenital adrenal cortex dysfunction (CACD)” was excluded.
30. Consultation with the Head of the Neurosurgical Department of the Regional Children Clinical Hospital on January 26, 2022 was the following: the child did not need neurosurgical treatment.
31. Consultation with a pediatric infectious disease specialist on January 25, 2022 was the following: damage to the CNS was assumed, probably due to previous intrauterine encephalitis with the formation of symptomatic epilepsy, internal hydrocephalus, periventricular leukomalacia, and a focus of epileptic activity.

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:

• infusion therapy included intravenous drip through a perfusor 10% glucose with components, 10% aminoven infant, and 20% SMOFlipid;
• heparin therapy “heparin lock” was performed with 10 units 2 times a day;
• antibacterial therapy involved intravenous cefepime from January 12 to January 19, 2022, meropenem (pharmameropen) from January 19 to January 24, 2022, doripenem (sanocef) from January 24 to February 13, 2022, vancomycin from January 19 to February 13, 2022, amikacin from February 5 to February 13, 2022 in combination with antifungal therapy with intravenous fluconazole (January 12 – February 12, 2022, and February 5–12, 2022) every 48 hours;
• vitamin therapy was accomplished with intramuscular pyridoxine, alternating with thiamine chloride from January 12 to February 1, 2022);
• correction of hypoalbuminemia with an intravenous drip of 20% albumin No. 3;
• diuretics by intravenous jet injection of furosemide No. 3; January 12, 13, and 14, 2022;
• correction of anemia was performed by intravenous drip of erythrocyte suspension 0(I) Rh (+) No. 2);
• symptomatic therapy;
• passive immunotherapy was carried out by intravenous drip immunovenin; January 21, 2022, February 7, 2022;
• biological preparations included bifidum bacterin, 5 doses 3 times a day from January 12 to February 12, 2022;
• immunomodulatory therapy was performed with interferon alpha-2b + taurine suppositories (Genferon Light suppositories) 125,000 IU in the morning and evening rectally from January 15 to January 30, 2022; then from January 30, 2022 every other day on odd days;
• Aquadetrim was taken enterally, 1 drop 1 time per day from January 18 to February 12, 2022;
• anticonvulsant therapy included valproic acid (depakine syrup) at a daily dose of 30 mg/kg (by 0.8 ml 2 times a day) from January 12 to January 19, 2022 and from January 19 to February 4, 2022 at a daily dose of 40 mg/kg (by 1.2 ml 2 times a day),
• depakine syrup at a daily dose of 30 mg/kg in 2 divided doses (1 ml 2 times a day) + levetiracetam (keppra) at a daily dose of 4 mg/kg in 2 divided doses (0.8 ml 2 times a day) were taken from February 4 to February 12, 2022;
• hormone therapy included prednisolone 9 mg No. 1, hydrocortisone (cortef) by 2.5 mg 2 times a day from January 20 to February 12, 2022;
• antianemic therapy included iron III hydroxide polymaltose (ferrum lek) by 1 ml;
• metabolic therapy included levocarnitine (elkar 30%) 3 drops 2 times a day;
• hepatoprotective therapy included ursodeoxycholic acid (ursofalk) by 0.8 ml from February 4, cleaning of the eye slits with a furacilin solution, picloxidine drops (vitabact) by 1 drop 3 times a day in both eyes (after examination on the retinal chamber);
• protective regime, position on the ICU table, body temperature monitoring every 3 hours, changing body position every hour, performing postural massage when changing the body position, fixing the cervical spine by wearing a Shants collar, placing the head on an orthopedic “donut”, “figure-of-eight” bandages on the ankle joints;
• oxygen therapy included humidified oxygen through a face mask, through nasal cannulas under the control of cardiac monitoring when the saturation level decreases below 91%;
• enteral feeding through a tube with the “Similac NeoSure” mixture, 110 ml every 3 hours.

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

• Q87.8 Hereditary metabolic disorder from the group of peroxisomal diseases: Zellweger syndrome? Leukodystrophy?
• Q04.3 Congenital malformation of the brain: microgyria, subcortical leukomalacia, lack of differentiation of white and gray matter of the brain, retrocerebellar cyst, hypoplasia of the corpus callosum with the development of hydrocephalic atrophic syndrome, periventricular gliosis of the white matter, symptomatic epilepsy, delayed psychomotor development, and sensorineural hearing loss.

Associated clinical diagnoses:

• P52.1 Combined perinatal hypoxic-ischemic-hemorrhagic (bilateral IVH of grade 2), unspecified viral-bacterial (Klebsiella) CNS lesion with the development of hypertensive-hydrocephalic syndrome, early neonatal convulsions (polymorphic generalized tonic-clonic ones), CNS depression syndrome, autonomic dysfunction syndrome, and pyramidal insufficiency syndrome.
• West syndrome with residual CNS injury?
• P39.8 Intrauterine infection of unspecified viral-Klebsiella etiology with the development of right-sided pneumonia, respiratory failure (RF I-0), mild anemia, and perinatal CNS injury.
• Q21.1 Functioning fetal communication: patent foramen ovale.
• Primary hypocorticism.

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:

1. The endocrinologist detected hypocorticism (adrenoleukodystrophy cannot be ruled out).
2. The neurologist revealed encephalomyelopathy (HMD from the group of peroxisomal diseases), epilepsy (metabolic) focal with evolution to generalized seizures; a single episode of hyperammonemia; muscle hypotonia syndrome, as well as paresis of the right foot; Bulbar dysfunctions; and Partial ptosis of the upper eyelid on the left.

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.