Pełny tekst: Clinical overlap and diagnostic difficulties in a patient with Lowe syndrome, Adam Jan Strzoda (2024)

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Pełny tekst: Clinical overlap and diagnostic difficulties in apatient with Lowe syndrome, Adam Jan Strzoda (1)

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Pełny tekst: Clinical overlap and diagnostic difficulties in apatient with Lowe syndrome, Adam Jan Strzoda (7)

1/2024
vol. 99

Opis przypadku

Adam Jan Strzoda

1

,

Aleksandra Sobieszczańska-Droździel

2

,

Magdalena Kamińska

1

  1. Student’s Scientific Group at theDepartment ofPaediatric Nephrology, Medical University, Lublin, Poland
  2. Department ofPaediatric Nephrology, Medical University, Lublin, Poland

Pediatr Pol 2024; 99 (1): 89 -93

Data publikacji online: 2024/03/05

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- Clinical overlap.pdf[0.18 MB]

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INTRODUCTION

Theidentification ofpatients with an ultra-rare disease is adiagnostic challenge, particularly when other disorders with symptoms overlapping its phenotype coexist. Sometimes only intuitive hunches, followed by analytical reasoning, make an accurate diagnosis possible. In contrast to routine practice, theart ofdifferential diagnosis is to recognise crucial patterns ofsymptoms, manipulate theprobabilities, and select themost accurate cause ofthepatient’s condition. Theauthors present a2.5-year-old boy with Lowe syndrome (LS) caused by apathogenic variant in theOCRL1 gene diagnosed at theage of16 months. Vitamin D3 overdosing and suspicion ofcongenital human cytomegalovirus (CMV) mimicked symptoms ofLS delayed an accurate diagnosis.

Statement ofethics

Written informed consent to publish thecase with accompanying images was obtained from theparents oftheaffected patient.

CASE REPORT

We report on a2.5-year-old boy ofPolish descent referred to theDepartment ofPaediatric Nephrology at theage of8 months due to nephrocalcinosis, considered aconsequence ofvitamin D3 toxicity. Thepatient is thefirst child ofnon-consanguineous healthy parents born in the37th week ofpregnancy by caesarean section due to foetal arrhythmia. Thepregnancy was complicated by themother’s flu-like infection in thefirst trimester, while thefamily history was uneventful. Apgar score was 10, body weight and length, and head circumference were 3300 g (25%), 55 cm (90%), and 32 cm (2%), respectively. At theage of 3 months, theparents observed nystagmus and alack offixation. Abinocular cataract was then diagnosed and operated on soon after. Global hypotonia, psychomotor retardation, and poor weight gain prompted themother to increase his vitamin D3 daily dose to 2000 IU at theage of5 months. Due to clinical deterioration, diagnostics were carried out in local hospitals. Congenital CMV, anaemia, hypercalcaemia (max. 3.55 mmol/dl), 25-hydroxy-cholecalciferol (25-OHD3) increased > 100 ng/ml, parathormone decreased to 4 pg/ml, leukocyturia (20–30 WBC/HPF), and proteinuria (150 mg/dl) considered as urinary tract infection were found. Theultrasound revealed nephrocalcinosis, and consequently thepatient was referred to theDepartment ofPaediatric Nephrology. On admission, his length, weight, and head circumference were < 3% (76 cm, 6.3 kg, and 42.4 cm, respectively). Thephysical examination revealed global hypotonia, umbilical hernia, pectus excavatum, and facial dysmorphia with awide forehead, prominent frontal eminences, deeply set eyeballs, and eyes slanted upwards (Figure 1).
Intoxication with vitamin D3 was confirmed and successfully treated (normalisation ofcalcaemia and cholecalciferol metabolites). Microcytic anaemia with low iron level and transferrin saturation index but normal ferritin required supplementation ofhaematopoietic drug: iron and B vitamins. On thefollow-up, sterile leukocyturia occurred periodically (Table 1).
Red blood cells, mean corpuscular volume, were 1,25-OHD3: 1,25-dihydroxyvitamin D3, 25-OHD3: 25-hydroxyvitamin D3, lactate dehydrogenase, aspartate aminotransferase, creatine kinase.
Increasing serum CMV IgG (50.9–78.9 U/ml) and thepresence ofCMV DNA in urine (5.6 ´ 105 IU/ml) and blood (7.8 ´ 102 IU/ml) were found. Conversely, CMV DNA was absent in thecerebrospinal fluid (CSF), and magnetic resonance (MRI) ofthehead and orbital cavities showed no significant abnormalities, which ruled out thepreviously suspected congenital cytomegaly. Amino acids and lactates in both serum and CSF were normal as well as GC-MS-based urinary organic acid profiling. Spinal muscular atrophy (SMA) and celiac disease were excluded. Theresult ofmicroarray-based comparative genomic hybridisation was irrelevant. Thefeatures ofincomplete Fanconi syndrome, such as persistent proteinuria of, hypercalciuria, aminoaciduria, and finally at theage of2 metabolic acidosis (HCO3 – 20.7 mmol/l, BE – 4.1 mmol/l) were treated symptomatically with hydrochlorothiazide (0.4 mg/kg/day) and bicarbonates (80 mg/kg/day). Simultaneously an energy-rich diet was introduced. Suspected at thetime, LS was not primarily confirmed by analysis ofexon 15 in theOCRL1 gene at theage ofone year. However, 4 months later thewhole-exome sequencing revealed ahemizygous novel pathogenic variant c.832C > G in theOCRL1 gene and confirmed theinitial diagnosis. Thesame heterozygous mutation was found in theproband’s mother.
Currently, at 2.5 years old, ultrasonographic features ofbilateral nephrocalcinosis remain stable in thesecond stage according to Hoyer’s ultrasound staging. Additionally, a5 mm long stone was found in themiddle calyx oftheright kidney (Figure 2). Theboy’s weight, height, and head circumference are < 3% (80 cm, 9.1 kg, and 44 cm, respectively). Thepatient presented global hypotonia and psychomotor retardation as he began to sit down, stand up, and walk (with assistance) at theage of18 months, 20 months, and 22 months, respectively. Mental and speech development remains moderately impaired. He does not report physiological needs, uses single words, and presents auto-aggressive behaviour – impulsive head-hitting (Figure 1). Multi-specialty care, personalised, intensive rehabilitation, and eyepiece correction are necessary. Thepatient is treated symptomatically with hydrochlorothiazide, sodium bicarbonate, and potassium chloride.

DISCUSSION

Lowe syndrome (oculocerebrorenal syndrome of Lowe – OCRL, OMIM #309000) is an ultra-rare X-linked recessive multisystem disorder with aprevalence of 1 : 500,000 in thegeneral population. It primarily occurs in males and is caused by mutations in theOCRL1 gene on chromosome Xq26-25, which encodes phosphatidylinositol 4,5-bisphosphate 5 phosphatase, theprotein primarily present in theGolgi complex, lysosomes, and endosomes [1–4]. TheOCRL1 gene is believed to be responsible for various cellular processes; however, membrane trafficking and actin cytoskeleton remodeling seem to be themost important. Proximal tubular cells, neurons, and lens epithelial cells have above-average rates ofendocytosis and are therefore prone to loss ofOCRL1 gene function [3, 4]. Consequently, in patients with LS, theeyes, nervous system, and kidneys are mainly affected [1–3]. Typical clinical manifestations include infantile glaucoma, congenital cataracts, areflexia, muscular hypotonia, intellectual disability, and renal proximal tubulopathy, ultimately leading to end-stage renal disease (ESRD) between thesecond and fourth decades oflife [1]. Mathematic and animal models suggest that thepathogenic variants in theOCRL1 gene impair theregeneration ofproximal tubules, which leads to their shortening and could explain renal symptoms such as low-molecular-weight proteinuria, aminoaciduria, hypercalciuria, and renal tubular acidosis [4]. Thus, persistent proteinuria and hypercalciuria, observed in thepresented patient from thefirst admission to our department, are typical renal manifestations ofLS. Due to theabnormal muscle metabolism ofour patient, elevated lactate dehydrogenase, serum creatinine kinase, and aspartate transaminase were partially observed, which are typical for LS (Table 1). Later, at theage of2 years, metabolic acidosis completed theclinical picture. Thecorrect diagnosis was initially blurred by overlapping symptoms caused by avitamin D3 overdose. Hypercalciuria in thepresented patient could be associated with vitamin D3 intoxication as well as nephrocalcinosis, although thelatter is rarely observed (about 10% ofcases) [5]. Thelatest Polish recommendations on daily intake ofcholecalciferol for children 0–5 months old are 400 IU/day and for 6–12 months 400–600 IU/day [6]. Thedose taken by thepresented patient was 5 times higher, and similar cases described in theliterature resulted in hypercalcaemia and hypercalciuria [7]. Theoverdosing was confirmed by thetoxic level of25-OHD3 and decreased parathyroid hormone level.
Hypercalcaemia and low parathormone are not observed in LS, while urolithiasis and nephrocalcinosis are found in about 22% and 52% ofpatients, respectively [8]; both may lead to sterile leukocyturia observed periodically in thepresented patient [9].
Interestingly, thecongenital cataract observed in our patient together with thehigh titre ofserum anti-CMV IgG (50.09 U/ml) and thepresence ofCMV DNA in urine and blood suggested perinatal CMV infection, which is an obvious cause ofacataract [10, 11]. Moreover, 1 in 3 cases ofcongenital cataracts is not aconsequence ofthesystemic disorder, so thebinocular cataract in our patient was initially linked to cytomegaly [12]. Further research revealed theabsence ofCMV DNA in theCSF and thelack ofcharacteristic abnormalities in thebrain MRI, which indicated postnatally acquired cytomegalovirus infection. Other symptoms present in our patient and common in infants with congenital CMV infection include anaemia, mental retardation, and microcephaly [11]. Our patient’s mother had ahigh titre ofanti-CMV IgG (414 U/ml) and negative anti-CMV IgM (0.14 U/ml) in thefirst trimester. Thus, with high probability, we can rule out themother’s CMV infection during pregnancy.
Thefirst genetic testing for LS was negative and directed thediagnostic reasoning toward another cause ofsymptoms observed in thepresented patient, such as poor neurodevelopment, hypotonia, and low weight gain. Consequently, SMA, celiac disease, galactosemia, and other metabolic diseases were ruled out. Thepathogenic variants oftheOCRL1 gene include deletion, missense, and nonsense mutations that may relate to thedifferent parts ofthegene resulting in various genotypes and phenotypes [13]. Moreover, even theaffected members ofthesame family may present different symptoms, and thecorrelation between thetype ofmutation and theseverity ofthedisease is not confirmed [14]. Many symptoms ofLS are nonspecific and appear only in some oftheaffected patients.
Our patient had prominent frontal eminences and deeply set eyeballs (Figure 1) which are typical in LS; however, other characteristic symptoms such as dental anomalies, tendonitis, and cryptorchidism were not observed in thepresented patient [2]. Although theprognosis in LS is uncertain, thedisease inevitably leads to ESRD. Thetreatment is mostly symptomatic, and multidisciplinary care with extensive rehabilitation are necessary.

CONCLUSIONS

Thepresented case shows diagnostic difficulties in apatient with LS and overlapping comorbidities. Comprehensive analysis ofclinical symptoms and detailed genetic evaluation enabled correct diagnosis and appropriate management.

DISCLOSURE

Theauthors declare no conflict ofinterest.

REFERENCES

1. Loi M. Lowe syndrome. Orphanet J Rare Dis 2006; 1: 16.

2. Bökenkamp A, Ludwig M. Theoculocerebrorenal syndrome ofLowe: an update. Pediatr Nephrol 2016; 31: 2201-2212.

3. Mehta ZB, Pietka G, Lowe M. Thecellular and physiological functions oftheLowe syndrome protein OCRL1. Traffic 2014; 15: 471-487.

4. Gliozzi ML, Espiritu EB, Shipman KE, et al. Effects ofproximal tubule shortening on protein excretion in aLowe syndrome model. J Am Soc Nephrol 2020; 31: 67-83.

5. Marcinowska-Suchowierska E, Kupisz-Urbańska M, Łukaszkiewicz J, et al. Vitamin D toxicity-aclinical perspective. Front Endocrinol (Lausanne) 2018; 9: 550.

6. Płudowski P, Kos-Kudła B, Walczak M, et al. Guidelines for preventing and treating vitamin D deficiency: a2023 update in Poland. Nutrients 2023; 15: 695.

7. Talarico V, Barreca M, Galiano R, et al. Vitamin D and risk for vitamin Aintoxication in an 18-month-old boy. Case Rep Pediatr 2016; 2016: 1395718.

8. Zaniew M, Bökenkamp A, Kolbuc M, et al. Long-term renal outcome in children with OCRL mutations: retrospective analysis ofalarge international cohort. Nephrol Dial Transplant 2018; 33: 85-94.

9. Szmigielska A, Krzemień G. Sterile leukocyturia – difficult diagnostic problem in children. Dev Period Med 2017; 21: 139-143.

10. Mansoor N, Mansoor T, Ahmed M. Eye pathologies in neonates. Int J Ophthalmol 2016; 9: 1832-1838.

11. Chiopris G, Veronese P, Cusenza F, et al. Congenital cytomegalovirus infection: update on diagnosis and treatment. Microorganisms 2020; 8: 1516.

12. Zetterström C, Kugelberg M. Paediatric cataract surgery. Acta Ophthalmol Scand 2007; 85: 698-710.

13. Lin T, Orrison BM, Leahey AM, et al. Spectrum ofmutations in theOCRL1 gene in theLowe oculocerebrorenal syndrome. Am J Hum Genet 1997; 60: 1384-1388.

14. Zhou FQ, Wang QW, Liu ZZ, et al. Novel mutation in OCRL leading to asevere form ofLowe syndrome. Int J Ophthalmol 2019; 12: 1057-1060.

Copyright: © 2024 Polish Society of Paediatrics. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.

Pełny tekst: Clinical overlap and diagnostic difficulties in a patient with Lowe syndrome, Adam Jan Strzoda (2024)

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