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15MEDICAL SCIENCES
ZELLWEGER'S SYNDROME, CLINICAL CASE, A WAY TO
THE DIAGNOSIS
Tychkivska O.
Department of Pediatrics and Neonatology, Lviv National Medical University
Korzhynskyy Yu.
Department of Pediatrics and Neonatology, Lviv National Medical University
Rudkovska I.
Neurology Department, Lviv City Communal Children's Hospital
Kuksenko O.
Neurology Department, Lviv City Communal Children's Hospital
ABSTRACT
Zellweger Syndrome Spectrum (ZSS) is a peroxisomal disorder that manifests in early infancy with an estimated incidence of 1:50,000. Classic Zellweger's Syndrome (ZS) is the most severe form from this spectrum a nd is a multiple congenital anomaly syndrome characterized by craniofacial abnormalitites, eye abnormalities, neuronal migration defects, hepatomegaly, chondrodysplasia punctata, and near-complete absence of peroxi-somes.[2,3,4,5] Definitive diagnosis is supported by specific laboratory tests. Treatment is only supportive for ZS. In this article one clinical case of ZS with a complicated way of recognizing the diagnosis is reported.
Keywords: Zellweger syndrome, neonatal seizures, leukodystrophy.
Introduction. Peroxisomes play an important role in numerous metabolic processes, but primarily the metabolism of fatty acids, in humans. Therefore, any genetic mutation that leads to an alteration of the proteins that compose peroxisomes will result in the development of various peroxisomal disorders with severe metabolic disturbances. Peroxisomal disorders are divided into two groups:
- Peroxisomal biogenesis disorders (PBDs), in which a mutation in any of the peroxisome assembly (PEX) genes promotes a total absence of peroxisomal function. The Zellweger syndrome spectrum (ZSS) (Zellweger syndrome , neonatal adrenoleukodystrophy, and infantile Refsum) and rhizomelic chondrodysplasia punctata are found within this group.
- Single peroxisomal enzyme deficiencies, which are syndromes that affect only one of the multiple pe-roxisomal functions. X-linked adrenoleukodystrophy, the adult form of Refsum, and pseudo-rhizomelic chondrodysplasia are found within this group. [1]
Among these syndromes, ZSS is the most severe, causing death within the first year of life. It was previously categorized as three distinct diseases (ZS, neonatal adrenoleukodystrophy, and infantile Refsum disease), but is now known to be a single condition with a varying spectrum of phenotypic severity. ZSS pheno-type is caused by mutations in PEX genes involved in peroxisomal biogenesis.[1,3,4,5] Diagnosis is made basing on VLCFA, phytanic acid, pristanic acid and plasmalogen plasma levels.[3] Dysmorphic craniofa-cial features such as high forehead, hypoplastic supraorbital ridges, epicanthal folds, midface hypoplasia, and large fontanel may be noted shortly after birth. Head circumference usually is normal. Child also develops encephalopathy, hypotonia, hypore-flexia.[2,3,4,5] Severe weakness and hypotonia mani-
fest in the neonatal period, in 80% accompanied by seizures, and apnea. Seizures are often partial, myoclonic or atypical flexor spasm, originating in arm, legs or face, these seizures usually do not culminate in generalized seizures and are easily controlled with medication. The interictal EEG of patients with ZS shows infrequent bilateral independent multifocal spikes, predominantly in the frontal motor cortex and surrounding regions. Hypsarrhythmia is observed sometimes too. [3] Multisystem abnormalities of the brain, kidneys, liver, skeletal system and eyes may occur. Eye abnormalitites include cataracts, glaucoma, corneal clouding, optic nerve hypoplasia, pigmentary retinal degeneration and Brushfield spots. [2,4,5] Most affected infants have oromotor dysfunction and require tube feeding. Hepatomegaly (reported in 78% of patients) with periportal fibrosis may result in significant cholestasis (in 59%) and jaundiceLatter along with hypotonia and dys-morphic features may cause confusion in the diagnosis of Down syndrome. Neuroimaging findings can include pachygyria, polymicrogyria localized to the opercular region and cerebellar heterotopias, laminar discontinuities involving the olivary nucleus. .[3] Little psychomotor development ensues..
Presently, only symptomatic treatment is available for this condition. The average life span has been reported to be 12,5 weeks.[2,3,4,5]
Case report: Child was hospitalized to the NICU department on the 2nd day of life after several episodes of apnoe with saturation drops (after the last one child needed permanent oxygen administration through nasal cannula) and cluster of multifocal clonic seizures followed by horizontal nystagmus. Seizures were stopped by Diazepam injection. At admission to NICU child also had an impaired level of consciousness, moderate generalized muscle weakness, hyporeflexia, decreased pupillary reactivity. Due to the secondary sucking
weakness and poor tolerance of enteral regimen child was fed through the nasogastric feeding tube partly and partly parenterally. After detailed examination both sides retinal bleedings, narrow auditory channels, right-sided cryptorhism, large big fontanelle (4,5 *4,5cm) and opened little fontanelles 1,5*1,5cm and sagittal suture widening up to 0,5 cm were revealed.
From the patient's medical records it was known that child was born from the third pregnancy, second delivery with 39 weeks of gestational age, BW - 3060g. There was one child with atopic dermatitis in this family already (born 6 years ago), and the second pregnancy (2,5 years ago) was interrupted by spontaneous abortion on the 15th week of pregnancy. 3rd Pregnancy course was complicated with the episode of acute pyelonephritis on the 23rd week of pregnancy, polyhydram-nios. Delivery was physiological, fast, with meconium-stained fluid and Apgar score 6\8. Child was noticed to have a mild hypotonia together with sucking weakness right after birth.
Upon admission to NICU child was primarily diagnosed with hypoxic-ischemic encephalopathy (HIE), seizures syndrome. Perinatal infection was suspected.
As seizures relapsed and interictal EEG showed episodes of alpha-activity 8-9 Hz in fronto-temporal regions from the right, 3-5 s runs of high-amplitude sharp waves in frontal regions (D>S), sporadic sharp waves in temporal and parietal regions predominantly from the right, child was loaded with Phenobarbital and then left on the maintance dose of 5mg/kg, what helped to achieve control over seizures. For the 24h period after admission child still needed oxygen therapy and clinically was severely hypotonic, reflexes were significantly diminished; episodes of horizontal nystagmus were still present. Interictal EEG background activity was suppressed with sporadic high-amplitude sharps in all parts of the brain more frequent in parietal and temporal regions (>5/min).
Ultrasonography of the brain revealed diffuse increase in parenchyma and thalami echogenicity, slightly enlarged lateral brain ventricles, subependymal thalamic hemorrhages.
Ultrasonography of internal organs was normal. Echocardiography revealed PFO 3 mm. ECG was also with no pathological findings.
On the 3rd day of life another cluster of focal clonic seizures in the lower limbs happened and was accompanied with saturation drops, slow and deep breathing pattern. Diazepam was given to stop seizures. And vitamin B6 (100mg) added to the treatment course. Child stayed very hypotonic, with hyporeflexia and very poor response to stimuli.
CBC on the 3rd day of life revealed anemia (HGB 80 g/l) with thrombocytopenia PLT 86 /L. Urinalysis was normal. Electrolytes, glucosae, bilirun, transaminase, creatynin, urea blood levels, CRP, TORCH Ig G, M blood levels were normal. TSH, fT4, fT3, 17-OH-progesterone were normal too.
LP done on the 3 rd day of life revealed slightly elevated cytosis - 100 cells (Neutrophills) in 1 mm3, sugar level 2,13, protein level - 0,66 in CSF. Bacterial meningitis was suspected and antibiotics (amykacin and cefazoline) were prescribed in meningeal doses.
CSF PCR results for TORCH and bacteriological LP test came negative and the second CSF test done in 3 days after the 1st one was within normal ranges. Diagnosis of meningitis was rejected.
On the 6th day of life oxygenotherapy was stopped as no saturation drops were observed for the last 24 hours.
On the 7th day of life parenteral feeding was completely stopped and child was fully enterally fed with the mother's breast milk, but because of the remaining general weakness including sucking weakness child was bottle-fed. On the same day child was discharged from NICU and moved to the Pathology of Newborns Department for further diagnostic and treatment.
Auditory screening program revealed severe sensorineural hearing impairment.
Ophthalmologist consultation: horizontal nystagmus, retinal bleeding, congenital glaucoma suspected.
Genetic counseling was held at the age of 1 month and revealed 46XY, karyotype. Craniofacial features became more prominent: high forehead, hypoplastic supraorbital ridges, epicanthal folds, large fontanels, palm skin folds, nails hypoplasia. Child was recommended to perform Baby screening genetic test.
Child was discharged from the hospital with the moderate weakness (child was only bottled-fed with mother's milk), chin and limbs episodic tremor, episodes of horizontal nystagmus, poor weight gaining. Recommendations were given to continue Phenobarbital (5mg/kg/d), to follow rehabilitation program of early development.
After the discharge by parents' decision child was consulted by the specialist of alternative medicine. Phenobarbital was canceled and phytotherapy strated. In two days clinical seizures relapsed starting as clonic movements of the limbs going into status epilepticus. Child was admitted to the ICU department of the City Children's hospital. Seizures were brought under control by parenteral Diazepam. Because of permanent saturation drops child was administrated nasal cannula oxygen therapy. First examination after achieving seizures control revealed symmetrical generalized muscle weakness and hypotonia, generalized hyporeflexia, absent gaze fixation, eyes didn't follow the moving object, horizontal nystagmus, big fontanelle 4*4 cm, small fontanelle - 1,5*1,5 cm, hepatosplenomegaly, failure to thrive, stridor, dysembryogenic stigma. In biochemical blood profile elevated levels of ALT, AST, ALP, GGT were revealed, decreased blood sugar level to 2,56 mM/l. PCR to Hepatitis B and C viruses came negative. Interictal EEG showed low amplitude background activity with short runs of high-amplitude sharp waves in frontal, temporal and parietal regions, prolonged periods of high-amplitude delta (1Hz) in temporal and parietal regions, frequent sharp and slow wave discharges in fronto-temporal zones. ECG revealed signs of myocardial ischemia. On neurologists' recommendation Valrpoic acid (VA) as a second an-tiepileptic medication was added.
After the third dose of VA GI bleeding started: 3 episodes of haematamesis followed by melena and severe deterioration of the child's condition. VA was stopped and fresh frozen plasma together with vitamin
K were administrated to stop GI bleeding. Child's condition was stabilized and he was left on the only antiseizure medication - oral Phenobarbital (6,5 mg/kg/d).
By that time results of Baby screening genetic test came. There was revealed elevated concentrations of free carnitine (CO), tetradecanoic acid (C14), hydroxy-hexadecenoylcarnitine (C16:1 OH).
Taking into account medical examination data and medical records Zelleweger syndrome was suspected. Differential diagnosis (DD) list included Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency syndrome and Krabbe disease.
Child was recommended to start DHA and car-nitine supplements, vitamin D (1000 IU/d), Ca glu-conate (200 mg/d) and because of post stress hypoga-lactia MCT formula was added to every feeding (3050% of every feeding volume).
Cranial and orbital MRI was performed to help with DD. Signs of leukodystrophy were described: ventricles enlargement, periventricular pseudocysts, abnormal areas of white-matter hyperintensity in pyramidal tract, occipital lobes with bilateral thalamic involvement and in posterior part of the corpus callosum in T2 and FLAIR sequences. ZS was the leading diagnosis for planning further management strategy and prognosis determination.
By parents' and doctors' decision for the second opinion, further specific diagnostic tests, and management plan child was transported to Magdeburg University Children's Hospital after achieving common consensus with the Head of the Clinic.
During 2-months period before the planned date of admission to Magdeburg Hospital child was hospitalized two more times because of acute obstructive bronchitis episode and acute pyelonephritis. Episodes of infections were very hard to manage as every episode was followed by weight gaining which was hard to stop. Child couldn't tolerate the appropriate (to his weight and age) amount of breasmilk/ formula even though frequent small in portions feedings were introduced. Child used to have 1 or 2 episodes of short lasting clonic seizures per week, permanent stomach cramps and episodes of spontaneous desaturations . 2 weeks after acute pyelonephritis episode, US still revealed mild enlargement of both kidneys, and small kidney stone (2,5 mm in diameter) from the left. Overall no improvement in child's condition was noticed. On the opposite more organs were noticed to be involved.
At the age of 7 months child was hospitalized to Magdeburg University Children's Hospital
On admission a significant muscle hypotonia, and weakness, hyporeflexia (gripping reflex, Moro reflex, walking reflex, creeping reflex, magnetic reflex were negative), slightly enlarged fontanelles, narrow auditory channels, high palate, hepatomegaly, medium-size pupils with no reaction to the light, empty gaze, inconspicuous sucking reflex were revealed. Physical development parameters: body weight 5190 g, length 66 cm, head circumference 1 - 40.5 cm, head circumference 2 - 26 cm, chest circumference 40 cm. The goal of further diagnostic and management plan was to determine diagnosis, differentiating between peroxisomal storage
disease (Zellweger syndrome, neonatal adrenoleuco-dystrophy), Krabbe disease and a Pelizaeus-Merzbacher disease.
Lab test revealed slightly elevated level of HCT, decreased PLT and NEU levels, hypochromic anemia, slightly elevated levels of ALT, AST, ALP, Ig E, ACTH, PTT, thrombin with normal levels of electrolytes, lactate, creatinine, CPK, TSH, fT4, cystatin C, sodium, chloride, potassium, calcium, phosphate, uric acid, bilirubin, cholesterol , CK, lipase, gamma-GT, cholinesterase, magnesium, IgA, IgG, IgM, D-dimer, fibrinogen, INR, blood's total BB, total protein, albumin, globulin. Urinalysis revealed mild leukocyturia, erythrocyturia. A determination of very-long-chain fatty acids (VLCFA) revealed elevated levels of phytanic and pristanic acids.
Blood Phenobarbital level was in the lower normal range.
CSF analysis revealed no pathological changes.
EEG showed hypsarrhythmia-like pattern.
X-ray of the chest, Echocardiography revealed no pathological changes.
Ultrasonography of the brain revealed slightly enlarged ventricles with residual small periventricular cysts, signs of vascular sclerosis in the area of Syllvian fissure, abnormal gyration, corpus callosum hypo-plasia.
Ultasonography of the internal organs revealed 7mm stone in the left kidney, enlarged liver with homogenous structure.
Ophthalmological findings: glaucoma, corneal clouding, optic nerve hypoplasia, no foveal macular reflex detected.
ENT findings: hearing loss (high degree)
MRI revealed the signs of leukodystrophy.
MR Spectroscopy revealed decreased choline peak.
Child was diagnosed with ZSS. Though diagnosis was determined, molecular genetic testing was done to prove it and for future pregnancies plannning and with the recommendation of providing an appropriate palliative care for a child, he was discharged from the hospital.
At the age of 9 months child was hospitalized again with the recurrent episode of urinary tract infection (UTI) accompanied with oliguria. Ultrasonography revealed bilateral kidney enlargement and stones in both kidneys. Palliative conservative treatment (potassium citrate, antibiotics) was recommended with a temporarily positive effect. Child was left on Cefuroxime at discharge but in 3 weeks another episode of UTI with oliguria happened. Since that time child was on a permanent antibiotics therapy (cefotaxime, ceftriaxone, vancomycin and meropenem), but gradual deterioration of kidney function lead to the next hospitalization to ICU department. Child was on life-sustaining therapy in ICU department for 2 months and died at the age of 13 months because of renal failure and disseminated in-travascular coagulation.
Summarizing all clinical, biochemical and radiological findings child was diagnosed with Zellweger syndrome. Molecular genetic data proved the diagnosis later. The complicated step by step diagnostic way from
HIE, bacterial meningitis, to PBD filled with doctor's successes and failures. Among the most critical mistakes were prescribing Valproic acid to the child with affected liver that caused severe deterioration of liver function; and stopping antiseizure treatment after starting alternative nontraditional course of treatment what caused child going into continuous cluster of seizures. These mistakes could be fatal. The determination of the diagnosis was very important for understanding child's prognosis and organizing a proper palliative symptomatic care. One more important clue to remember is to consider rare conditions in DD list for the unclear case before starting treatment to make sure our steps are safe enough for a child.
Acknowledgement
To Professor Gerhard Jorch, Magdeburg University Children's Hospital, for invaluable help in diagnosis determination and recommendations for clinical management of a child, for sharing knowledge and experience.
References
1. Galvez-Ruiz A., et al. A clinical case of Zell-weger syndrome in a patient with a previous history of ocular medulloepithelioma. Saudi J Ophthalmol (2017), https://doi.org/10.1016/j.sjopt.2017.09.004
2. Pediatrics neurology: principles and practice / ed. by Kenneth F. Swaiman, Stephen Ashwal, Donna M. Ferriero. - 4th ed., 2012;1:740-744.
3. Wyllie's Treatment of Epilepsy: principles and practice/ ed. by Wyllie A., et al. - 6th ed., 2015:388389,397-398.
4. Zellweger Spectrum Disorders. NORD. September 15, 2008; http://www.rarediseases.org/rare-dis-ease-information/rare-diseases/byID/363/view-Abstract.
5. Zellweger spectrum. Genetics Home Reference. June 2015; http://ghr.nlm.nih.gov/condition/zell-weger-spectrum.
КРАНИОМАНДИБУЛЯРНАЯ ДИСФУНКЦИЯ - НОЗОЛОГИЧЕСКАЯ ЕДИНИЦА ИЛИ СОБИРАТЕЛЬНОЕ ПОНЯТИЕ?
Хабадзе З.С.
Российский университет дружбы народов, к.м.н., доцент
Балашова М.Е. Российский университет дружбы народов
студент
CRANIOMANDIBULAR DYSFUNTION NOSOLOGIC UNIT OR
COLLECTIVE CONCEPT?
Habadze Z.S.
Peoples' Friendship University of Russia Balashova M.E.
Peoples' Friendship University of Russia
АННОТАЦИЯ
В статье рассмотрены вопросы определения понятия «краниомандибулярная дисфункция» (КМД), использования термина в современной медицине. Обоснована и исследована проблема отсутствия точного понятия данной патологии, как симптомокомплекса, а не конкретной нозологии. Так как симптомы кра-ниомандибулярной дисфункции могут быть свойственны заболеваниям других областей тела, а не только поражениям челюстно-лицевой области, врачам-клиницистам необходимо это учитывать для поставки правильного диагноза, проведения дифференциальной диагностики и выбора подходящего плана лечения.
ABSTRACT
The article discusses the issues of the concept of "craniomandibular dysfunction" (CMD), the use of the term in modern medicine. The problem of the lack of the exact concept of this pathology as a symptom complex rather than a specific nosology is substantiated and investigated. Since the symptoms of craniomandibular dysfunction may be characteristic of diseases of other areas of the body, and not only lesions of the maxillofacial region, clinicians need to take this into account to supply the correct diagnosis, differential diagnosis and selection of a suitable treatment plan.
Ключевые слова: краниомандибулярная дисфункция, нозологическая единица, собирательное понятие, симптомокомплекс, функциональное расстройство, диагноз.
Keywords: craniomandibular dysfunction, nosologic unit, collective concept, symptom complex, functional disorder, diagnosis.
Многие клинические понятия, в настоящее время считаются "нозологической единицей", то есть определенной болезнью, имеющей установ-
ленную причину возникновения, механизм развития, характерные морфологические, функциональные, клинические проявления. На самом деле данные термины могут быть гетерогенными, то есть
