Patil, S

Ramanathan, G

English

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Syndromic Vignettes in Anaesthesia29SAJAA 2009;15(2) • Apr/May12A case of Lowe syndrome (oculocerebrorenalsyndrome): Clinical implications and anaestheticmanagementRamanathan G, MDPatil S, DNBDepartment of Anaesthesiology, Dr DY Patil Medical College and Research Centre, Navi Mumbai, IndiaCorrespondence to: Dr Gayathri Ramanathan, e-mail: gayathrii.r@gmail.com, gayathriir@yahoo.comIntroductionIn 1952 Lowe and his colleagues described a syndrome withorganic aciduria, decreased renal ammonia production,hydrophthalmos and mental retardation.1 In 1954, a renalFanconi syndrome was recognised as being associated withthe syndrome,2 and in 1965 an X-linked pattern of inheritancewas determined.3The oculocerebrorenal (Lowe) syndrome is characterised bycongenital cataracts, hypotonia, developmental delay, poorgrowth and renal tubular dysfunction. Clinical problems typicallyinclude polyuria, acidosis and hypophosphataemia with ricketsand eventually end-stage renal disease.4 Hypercalciuria and itssequel (nephrocalcinosis and nephrolithiasis), typical of distalrenal tubular acidosis, have not been described as cardinalfeatures of the untreated disorder although they reportedlycomplicate vitamin D and calcium therapy of rickets.4The disease is caused by the mutations of the OCRL gene whichis localised at chromosome Xq24-26, coding for enzymephosphatidyl inositol (4, 5) biphosphatase (Ptdlns (4, 5) P2phosphatase), responsible for transport of vesicles in the Golgiapparatus.5 Accumulation of phosphatidyl inositol (4, 5)biphosphate the main substrate for this enzyme in Lowe cells,and mutual disequilibrium of phosphoinositides cause the clinicalpicture at birth and possibly the later complications.6We report here the perioperative management of a child withLowe syndrome who was operated for congenital cataract.Case descriptionA three year old child diagnosed with Lowe syndrome wasscheduled for bilateral cataract extraction. He presented asunderweight, had delayed motor and mental milestones andwas hypotonic. He was the fifth born child to a non-consanguineous couple. His parents had already lost two children,both males, at the age of eleven and two months respectively,and both the children had hypotonia and cataracts.The child was mentally retarded and his speech was reducedto monosyllables. He had no history of seizures.This child was born out of a normal full term home delivery,and was noticed to have cataract at birth. He had delayedpassage of meconium. The parents reported that the child haddelayed motor milestones like neck holding and sitting. He usedto have frequent respiratory infections. The presence of hypotonia,congenital cataract, metabolic acidosis, and the death of twomale siblings who also had hypotonia and cataract led to a highsuspicion of Lowe syndrome in this patient. He was treated foracidosis with sodium bicarbonate tablets (soda Mint) in divideddoses with frequent blood analysis to maintain serum levelsaround 20 mmol.l.-1Figure 1: Case of Lowe syndromeOn examination child had microcephaly with frontal bossing,micropthalmos, his posture was limp and floppy and the feelof the muscles was flabby. The child was assigned a mental ageof six months.His body weight was 10 kg (below the third percentile) andhead circumference was 45 cm (below the third percentile).There were no involuntary movements, the deep tendon reflexeswere sluggish and plantars were flexors. Pulse rate, bloodpressure, respiratory and cardiovascular examination were withinnormal limits.All routine investigations (haemoglobin, random blood sugar,renal function tests and chest x-ray) were unremarkable. Renalultrasound did not show any evidence of nephrocalcinosis ornephrolithiasis.A thyroid function test was also advised to rule out congenitalhypothyroidism as the child had delayed passage of meconium,complaints of constipation, delayed milestones, and mentalretardation. T3, T4 and TSH values were within normal limits.Although alkaline phosphatase is usually elevated in Lowesyndrome (due to rickets resulting from the urinary loss ofphosphates), it was within normal limits in this case.SAJAA 2009; 15(2):  29-3130SAJAA 2009;15(2) • Apr/MaySyndromic Vignettes in AnaesthesiaThe child was kept starving for six hours prior to surgery andwas started on lactated Ringer’s solution 40 ml per hour toprevent dehydration. He was kept warm as hypothermia couldworsen acidosis. No premedication was given. General anaesthesiawas planned.  He was induced with thiopentone sodium 5 mg.kg-1. The trachea was intubated with uncuffed 4.5 sized trachealtube facilitated by atracurium besylate 0.5 mg.-1. Anaesthesiawas maintained with 50% each of O2-N2O, intermittent halothane(0.2–1%) with incremental doses of atracurium. Pain relief wasachieved with fentanyl 2 mcg.kg-1. Intraoperative blood sugarand arterial blood gas analysis were done which were againunremarkable.After the surgery, once spontaneous breathing returned,anaesthesia was reversed with neostigmine 0.05 mg.kg -1 andglycopyrrolate 6 μg.kg -1. Extubation was performed afterconfirming return of adequate motor power. He was observedin the PACU for 2 h before being transferred to the ward.DiscussionLowe syndrome is an uncommon, pan-ethnic disorder with theprevalence of only a few individuals per 100 000 births.7 It hasa recessive X-linked pattern of inheritance which typically affectsmale children, females acting as carriers. Penetrance iscomplete,with similar phenotype in the affected males withina given family. The diagnosis is established in affected individualsby demonstrating reduced (< 10% of normal) activity of inositolpolyphosphate 5-phosphatase OCRL-1 in cultured skin fibroblasts.8Congenital cataract can be a part of congenital syndromes, dueto chromosomal anomalies, systemic associations or prenatalinfections. A few are listed in Table I.At birth, ocular involvement with bilateral cataract and hypotoniamay be found in generalised congenital infections (rubella),peroxisomal disorders (Zell Eger syndrome spectrum), Nance-Horan syndrome, congenital myotonic dystrophy type 1,mitochondrial disorders and cystinosis.3,8Although the diagnosis of Lowe syndrome is not straightforward,virtually all patients have some degree of hypotonia with absenttendon reflexes and cataract at birth.1 Systemic Galactosaemia, galactokinase associations deficiency, hypoparathyroidism, pseudohypoparathyroidism, mannosidosis, cystinosis, peroxismal disorders, mitochondrial disorders, Smith-Lemli-Optiz syndrome andLowe syndrome2 Prenatal infections Congenital rubella, toxoplasmosis,cytomegalovirus, herpes simplexand varicella3 Chromosomal Downs, Patau and Edwardabnormalities syndrome4 Skeletal Hallermann-Streiff-Francoisabnormalities syndrome and Nance-Horan syndromeCongenital cataract may be associated with another paediatriccondition, galactosaemia. This is an X-linked recessive disorder,associated with deficiency of galactokinase enzyme. The infantshave problems of failure to thrive, aminoaciduria and mentalretardation, in addition to cataract. This child was initially treatedas a case of galactosaemia for the first few months of life beforethe diagnosis of Lowe syndrome was made. Hypotonia andmetabolic acidosis due to proximal tubular dysfunction differentiatethis condition from galactosaemia.Thyroid function tests were done to rule out hypothyroidism asthe child was mentally retarded, had delayed milestones andcomplaints of chronic constipation. The results showed normalT3, T4 and TSH levels.Early diagnosis of Lowe syndrome can be difficult. Low molecularweight (LMW) proteinuria, characterised by the excretion ofproteins such as retinol binding protein (RBP) and the lysosomalenzyme N-acetyl -glucosamidinase (NAG), are significantly raisedin boys with Lowe syndrome. LMW proteinuria can be seen earlyin life even in the absence of clinically significant aminoaciduriaor other renal abnormalities. Thus, LMW proteinuria may be themost sensitive marker of renal dysfunction that occurs in thisdisorder.9Hypotonia in these children often causes feeding difficulties.Sucking and swallowing may be impaired in the neonate makingthem susceptible for aspiration. These children are moresusceptible for developing pneumonia because of their hypotoniacausing inability to cough effectively. A high incidence of gastro-oesophageal reflux is also noticed. Although tone improves withage, patients never achieve normal muscle tone, and consequentlydevelop problems like hernia and scoliosis.The renal component of Lowe syndrome comprises type 2 renaltubular acidosis (RTA) (Renal Fanconi syndrome), where themain problem is greatly impaired reabsorption of bicarbonatein the proximal tubule. This results in urinary loss of HCO3-with inappropriately high urine pH. The bicarbonate is replacedby chloride in the circulation resulting in hyperchloraemicacidosis.10 The increased distal Na+ delivery results inhyperaldosteronism with consequent potassium wasting.Although hypercalciuria and nephrocalcinosis typical of Type1 RTA (distal RTA) are not cardinal features of Lowe syndrome,isolated cases are reported in literature. This picture can becomplicated in these children as they are put on calcium andvitamin D therapy making them more susceptible for stoneformation. Renal tubular functions may be normal a birth buttypical abnormalities are often detected by first decade of life.Glomerular function falls slowly with age, with renal failurepredicted between the second and fourth decade of life.Serum creatinine levels remain normal during the first decadeof life. As creatinine is made in muscles, the blood levels ofcreatinine lower than expected for a given degree of renal failuremay be observed as the muscle mass is reduced. A 24 hoururine creatinine or creatinine clearance gives a more accurateestimate of kidney functions.As the kidneys are not able to conserve water and concentrateurine normally, strict perioperative precautions to preventdehydration should be taken. Hypothermia can cause disturbancein peripheral circulation and worsen metabolic acidosis, so stricttemperature monitoring is advised.11Table I: Congenital syndromes associated with metabolic diseasesand prenatal infections31SAJAA 2009;15(2) • Apr/MaySyndromic Vignettes in AnaesthesiaThe most important problem affecting anaesthetic managementis chronic metabolic acidosis. Any agent that rapidly decreasesthe sympathetic tone, in the presence of acidosis may potentiatecirculatory depression. Since most opioids are weak bases,acidosis can increase the fraction of the drug in the non ionisedform and facilitate penetration of the opioid into the brain,causing increased sedation and respiratory depression.12As these children are already hypotonic, any degree ofhypokalaemia increases muscle weakness. It is recommendedto use short acting muscle relaxants like atracurium with nervestimulators to follow up the degree of paralysis and adequacyof reversal. A careful watch on K+ levels is recommended asserious cardiac arrhythmias can occur with hypokalaemia.12Although there is albumin loss in urine, it is usually not severeenough to cause nephrotic syndrome. A generalised aminoaciduriaalso usually does not cause any clinical problem, although ithelps in establishing the diagnosis.Loss of L-carnitine is associated with a decreased ability totolerate fasting, hepatomegaly and low blood sugar. Strictmonitoring of blood sugar is mandatory as hyperglycaemia andsecondary insulin secretion may further lower serum potassium.12A high arched palate, small mouth, crowding and poor alignmentof teeth secondary to rickets make intubations difficult in thesecases.Boys with Lowe syndrome are generally of normal length atbirth, but by one year of age most usually fall below the normalrange.3 These children are prone to vitamin D deficiency (rickets)as dihydrocholecalciferol of (vitamin D) is made in renal tubules,leading to a higher incidence of fractures. Rickets can be improvedby giving preparations of neutral phosphate or vitamin Dpreparation like calcitriol.The nervous system involvement causes problems includinghypotonia, intellectual impairment and behavioural problemslike tantrums, stubbornness, stereotypy and obsessions. Manychildren need long term anticonvulsants for seizure disorders.Cranial MRI may show ventriculomegaly and cysts in theperiventricular regions.Lowe syndrome is one of the rare conditions were congenitalcataract and glaucoma may co-exist. Corneal degenerationresulting in keloid formation can cause visual impairment laterin life. As many of these children have coexisting glaucoma itis preferable to use non-depolarising muscle relaxants forintubation as the use of the muscle relaxant succinylcholine canincrease the intraocular pressure. Implantation of an artificiallens is also not recommended because of the propensity todevelop glaucoma. Direct pressure on the eye from a tightlyfitting mask and poor prone position must be avoided as thesecan again increase intraocular tension.12Treatment is usually supportive like cataract extraction, speechtherapy, anticonvulsants and management of renal complications.3Bicarbonate therapy is used at the dose of 2–3 mmol.kg-1 perday every six to eight hours to maintain serum levels around20 mmol.l-1. The other drugs recommended are sodium orpotassium phosphates for correcting phosphate depletion andVitamin D to prevent rickets.These children can come to the operating room for congenitalcataract, glaucoma repair, corneal keloid excision and removalof corneal cysts at a very early age. Surgical correction ofundescended testis, hernia repair, fractures, correction of scoliosisand renal transplantation are the other surgeries usually performedin them.Metabolic acidosis and hypokalaemia are the important aspectsto be noted and should be appropriately corrected duringemergency situations. Preoperative ECG is necessary to showcardiac arrhythmias caused by hypokalaemia.12The diagnostic triad of the oculocerebrorenal syndrome of Loweincludes congenital cataract, neonatal or infantile hypotonia withsubsequent mental impairment, and renal tubular defects. Activityof the enzyme phospatydyl inositol (4, 5) biphosphatase can bemeasured in cultured skin fibroblasts to confirm the diagnosisin affected males.2Molecular genetic testing by sequence analysis of the OCRLgene identifies mutations in approximately 95% of males withLowe syndrome. Fish analysis can detect gene deletions.8Slit lamp examination is a highly accurate and sensitive test forcarrier detection.13 The typical findings are lenticular opacitiesor a single dense posterior cataract. Prenatal diagnosis of at-risk pregnancies is done using molecularanalysis of phospatidyl inositol triphosphatase (Ptdlns (4, 5) P2phosphatase) in cultured chorionic villi.The uneventful course of anaesthesia was related to thoroughsystemic evaluation and careful anaesthetic management.Conflict of interest: NoneAcknowledgementThe authors thank Dr Ashok Kumar, Senior Resident inAnaesthesiology, SRM Hospital and Research Centre,Kattangulathur, Chennai, India for redrafting and revising themanuscript.References:1. Lowe CU, Terry M, MacLachan EA. Organic acidurea, decreased ammoniaproduction, hydrophthalmos and mental retardation. Am J Dis Child.1952;83:164–184.2. Bickel H, Thursby-Penlam DC. Hyper-animo-aciduria in Lignac Fanconi disease,in galactosemia and in Obscure Syndrome. Arch Dis Child.1954;29:224–231.3. Richards W, Donnel GN, Wilson WA, Stowens D, Perry T. The Oculocerebralsyndrome of LOWE. Am J Dis Child. 1965;109:1854-203.4. Sliman GA, Winters WD, Shaw DW, Avner ED. Hypercalciuria and nephrocalcinosisin the oculocerebrorenal syndrome. J Urol. 1995;153:1244–6. [PubMed]5. Suchy SF, Olivos-Glander IM, Nussabaum RL. Lowe syndrome, a deficiency ofphosphatidylinositol 4, 5-bisphosphate 5- phosphatase in the Golgi apparatus.Hum Mol Genet. 1995;4:2245–50.6. Mario Loi. Lowe syndrome. Orphanet Journal of Rare diseases 2006;1:6.http://www.ojrd.com/content/1/1/167. Alan Lewis, Robert L Nussbaum, Eileen D Brewer. Lowe syndrome Gene reviews.Developed at university of Washington Seattle. Last revised on March 12, 2008.file:///F:/Lowe Syndrome -- Gene Reviews -- NCBI Bookshelf.htm8. Zhang X, Hartz PA, Philip E, ET al.Cell lines from kidney proximal tubules ofa patient with Lowe syndrome lack OCRL inositol polyphosphatase andaccumulate phosphatidylinositol 4, 5- biphosphatase. J Biol Chem.1998;273(3):1574-82.9. Laube GF, Russell-Eggitt IM, van't Hoff WG. Early proximal tubular dysfunctionin Lowe's syndrome. Arch Dis Child. 2004;89:479–80.10. Laing CM and Unwin RJ. Renal tubular acidosis. J Nephrol 2006. Mar-Apr;19Suppl 9 S46–52.11. Hisako Komatsu, Masatomo Sakakibara, Yutaka Yoshimura et al. Anaestheticmanagement for a patient with LOWE syndrome. Journal of Anaesthesia.1994;8:121–123.12. F.Sarica_lu et al Preoperative and perioperative management of a patient withLOWE syndrome diagnosed to have Fanconi’s syndrome. Pediatric Anesthesia.2004;14:530–532.13. Lin T, Lewis RA, Nussbaum RL.Slit lamp examination is a highly accurate andsensitive test for carrier detection in Lowe syndrome. Ophthalmology.1999;106:119–22.

A case of Lowe syndrome (oculocerebrorenal syndrome): Clinical implications and anaesthetic management

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A case of Lowe syndrome (oculocerebrorenal syndrome): Clinical implications and anaesthetic management

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