A very sick neonate with pancytopenia, profound

hypocalcemia and extreme hyperphosphatemia

Dr. CO Sham and Dr. K Tse (Cons., TMH)Prepared on July 2011

History

• Maturity 37 week and 5 days, birth weight 2.5 kg, delivered by Caesarean Section at St. Teresa Hospital because of maternal preference

• Both parents had known alpha thalassaemia trait, Mother alpha thal 1; Father alpha thal 2 Quong Sze (native city 'Kai-ping')

• Parents unrelated. • Mother also had chronic hepatitis B.

History

• Previous child died at Tuen Mun Hospital in April 2008 on second day of life because of meconium aspiration, pulmonary hypertension of newborn and Hb H disease.

• Antenatal course of the current pregnancy was uneventful. Followed up both at O&G, Tuen Mun Hospital and private O&G doctor.

• Baby was well after delivery.• Hepatitis B vaccine and HBIG were given shortly after

delivery, and BCG given over left shoulder on 16-4-2011.• Baby was FU daily by a private Pediatrician in first 7

days of life. Told to be normal all along. A strong odour was noted since birth by the family, but the parents were told that it was normal.

Current admission

• Admitted via A&E, TMH on Day 14 of life at 1:24 am because of cough, shortness of breath and poor feeding for 1 day

• No fever all along• Decreased feeding from 30 ml X 6 per day down to 15

ml X 4 in 1 day• Decreased urine output and no bowel opening for 1 day• Seen by a private doctor at Tuen Mun, given ibuprofen,

infacol, piriton, U-Eaton, domperidone and pro-amine, but the condition did not improve. Therefore, the parents brought the child to A&E

• No sick family members• No recent travel outside Hong Kong

Physical examination

• Tired looking with fair general condition• Capillary refill 2 seconds• Dry oral mucosa with normal skin turgor• BW 2.42 kg (birth wt 2.5 kg), BH 47 cm,

HC 34 cm• Respiratory rate 50/min; Apical rate

140/min• Axillary temperature 36.4∘C

Physical examination

• Left shoulder: normal looking, and BCG scar not seen

• Chest: subcostal insucking with decreased air entry over right middle zone

• CVS: normal heart sound, no murmur• Abdomen: soft and distended, liver 2 cm

below costal margin, no splenomegaly, bowel sound active

• CNS: AFNT• Skin: no rash

Family tree

Paternal grandfather58-year-old

Paternal grandmother56-year-old

Paternal uncle30-year-old

Father31-year-old

Mother30-year-old

Maternal grandfather66-year-old

Maternal grandmother58-year-old

Maternal uncle34-year-old

Maternal uncle35-year-old

Died on 2nd day of life in 2008 because of pulmonary hypertension of newborn and Hb H disease.

Miscarriage at 9th week gestation in

May 2010 Our patient

Chest x-ray

Progress

• Sepsis work up performed including blood culture, lumbar puncture and bladder catheterization

• First venous blood gas: pH 7.30, pCO2 3.5, pO2 5.1, BE -12.2

• 2 boluses of normal saline 10 ml/kg given• Started on ampicillin, and cefotaxime, which was

later switched to meropenem• Also started ranitidine in view of brownish

substance aspirated from Ryle's tube

Arterial blood gas

Clotting profile

Deterioration

• At 8:50 am on the same day, in view of increase oxygen requirement, pallor, and septic looking baby with neutropenia, severe hypocalcaemia, hyperphosphataemia, acute renal failure and decompensated metabolic acidosis, baby was transferred to NICU for further care.

• Convulsion at 10:00 am at NICU, presented as staring eyes and tonic contraction of 4 limbs. Attack lasted for 30 minutes, stopped by phenobarbitone and bolus of calcium gluconate.

• ECG monitoring once showed ectopic beats, but not found on ECG long lead II after calcium supplement given

Acute stage

• Double lumen PICC was set via the right long saphenous system

• Later the baby was intubated and put on mechanical ventilation for poor respiratory effort

• Active bleeding was found from endotracheal tube and Ryle's tube

• Repeated transfusions of platelet concentrate, fresh frozen plasma, and vitamin K to stop bleeding. Given pack cells to top up hemoglobin.

• Calcium supplement was given, and hyper-phosphataemia improved with hyperhydration

Correcting electrolyte disturbance

Correcting electrolyte disturbance

In the middle of the night

• Baby dull looking and no response to pain

• No sedation all along

• Glasgow Coma Scale 3/15 (E1V1M1)

• ? Fixed and dilated pupil

• Limb hypotonic but reflexes present

• Gag reflex present but hyporeflexic

• Urgent CT brain arranged

CT brain

After baby's condition improved, subsequent CT brain revealed diffuse cerebellar hemorrhage. Seen by neurosurgeon – baby unlikely to benefit from clot evacuation.

Next morning

• Baby still in “comatose” state

• No response to voice and pain

• Pupils equal but sluggish response to light

• Nurse reported foul smell inside the incubator

• Cerebrospinal fluid and catheterized urine cell counts, and biochemistry indicated that infection was not likely

Stop and think!• Previous baby died of thalassaemia and

PPHN• We are now facing a baby with:

‘Good past health’ Day 14 babySevere metabolic acidosisPancytopeniaSevere hypocalcaemia and hyperphosphataemiaFoul smelling odourCerebellar hemorrhageNo response to pain and voice

Differential diagnosis

• Severe infectionPyogenic infectionViral infection (HBV, HPV)Disseminated BCG infection in immuno-

compromised host

• Tumor lysis syndrome

• Inborn error of metabolism

• Congenital heart diseases

Help from colleagues of other disciplines

• Seen by microbiologist, suspect disseminated herpes simplex infection in view of pneumonia, pancytopenia and derange liver function

• Mother had a cold sore over her upper lip

• Started on IV acyclovir

• (Virus study turned out to be negative)

• Blast cells not detected x 2 in P’ smear

The alarming result

Metabolic screening (28-4-2011)

Urine organic acid profile

• Significant hyper-excretions of isovaleryl-glycine and 3-hydroxy-isovaleric acid and presence of 4-hydroxyisovaleric acid, methylsuccinic acid and mesaconic acid were detected.

• The pattern is diagnostic of isovaleric acidemia.

Plasma amino acid (28-4-2011)

Reference: http://www.newbornscreening.info

Reference: http://www.medscape.com

Isovaleric acidemia (異戊酸血症 ) in the East Asia

• At least 7 cases in Taiwan

• No new cases after newborn screening for metabolic diseases

• Autosomal recessive inheritance

• Antenatal screening can be offered

http://www.genes-at-taiwan.com.tw/genehelp/database/disease/IVA_940830.htm

Treatment

• Started on L-carnitine and L-glycine once diagnosis was confirmed.

• Glasgow Coma Scale improved gradually• Started on parenteral nutrition with low

levels of amino acids. Later switched to protein free formula.

• Gradual step up amount of protein in diet• Monitor ammonia (daily) and carnitine levels

The happy result

Treatment

• Train up oral feeding

• Serial USG brain revealed hematoma resolved gradually

• Neuro-developmental training offered

• Follow up to monitor development

• Antenatal counseling to parents for next pregnancy (alpha thalassaemia and isovaleric acidemia)

Future follow up plan

• Educate parents and medical team about the presentation of metabolic decompensation

• Symptoms and signs: Ill looking childFeverSweaty feet odourRecurrent vomiting, diarrhea, severe dehydrationTachypnoeaHypothermiaListlessness, lethargy, seizures and comaStroke manifestations, encephalopathy

Stress that may trigger the problem

• Increased protein / leucine (rice with high leucine content) intake

• Poor diet compliance • Fever and acute

infections• Gastroenteritis• Pancreatitis• Vaccinations

• Episodes of increased catabolism

• Prolonged fasting • Surgical and dental

procedures• Trauma (severe)• Strenuous exercise

training • Graves’ disease

Counseling & referrals • Counseling by management team, chemical pathologist, then

dietician• Written information was given to parents (異戊酸血症 )• The sick day plan• Letters to concerning GPs• CMS entries, reminders, drug alerts

• Special nurses / ward for further admission• Dietician, speech therapist, physiotherapist and occupational

therapist• Child Assessment Center, Eye clinic• Financial problem, the special formula, IVA anamix infant, is very

expensive (> $600 / can for long-termed use)

Further points for discussion

• Lab monitoring

• Misleading presentations

• Remove the toxic metabolites

• Emergency Tx and cautions

• Problems on long-termed FU

• Diets

• Patient group

AJHG 2004; 75: 1136-42

AJHG 2004; 75: 1136-42AJHG 2004; 75: 1136-42

AJHG 2004; 75: 1136-42

Misleading presentations in neonates

• Premature infant (32 wk) might have normal serum ammonia level during attack

• Sepsis in neonate (E coli) (stop and think even with +ve culture)• Recurrent / severe vomiting (leading to pyloromyotomy) (vomiting not

improved) • Feeding difficulty, diarrhea, severe dehydration, wt loss, tachypnea,

hypothermia, cholestasis, abnormal posturing and movement, spasm, listlessness,

• Lethargy, seizures, coma, stroke manifestations, encephalopathy, leading to death / severe brain damage within a few days if not treated promptly.

• Isomil with lower leucine (may present later)

• High index of suspicion – characteristic smell of ‘sweat feet’, keto-acidosis, large anion gap, high serum ammonia levels (premature baby?) (dry blood spot test can show the metabolic defect)

Presentations in late onset cases

• FTT, selective refusal of protein-rich foods, periodic vomiting, alopecia • ‘Dirty sock’ / unwashed body’ / ‘sweaty feet’ odor +/- smells of ketones in

breath during attacks• Abnormal behavior / ‘psychosomatic’ attacks after meal / in afternoon

(rather than in the morning)• Learning difficulties, isolated cognitive impairment, developmental delay,

mental retardation, needs of special school. • Movement disorders (tremors, choreoathetosis, dystonia), seizures,

generalized hypotonia, intermittent ataxia, repeated acute episodes, abnormal postures / movements / behavior

• Dizziness and blurred vision and unsteady gait in teenager; • Constipation, abdominal distension / pain, pancreatitis. • Fanconi syndrome, proximal RTA, hyperchloremic metabolic acidosis. • Secondary carnitine def. as heart failure, conduction disturbances,

sensitivity to other potentially cardiotoxic medications. • Dwarfism, cataract and congenital abnormalities. • Some may attend normal school, attending college / university, +/-

independent life.

Other misleading presentations

• Late onset cases may have huge hyperammonaemia (200 – 1400 μM), without ketoacidosis, mistaken as urea cycle disorder

• Leukothrombocytopenia +/- anemia / pancytopenia / extra-medullary hematopoiesis, resembling promyelocytic leukemia, (no blast cells in [repeated] peripheral smear, 15:17 translocation not present), arrest of myeloid series at the promyelocytic stage, isovaleric acid is toxic to bone marrow

• Hyperglycemia (mistaken as DKA, but very sensitive to insulin, normal Hb A1c, repeated episodes)

• Stoke manifestations, intra-cranial / ventricular / cerebral / cerebellar bleeding, +/- brain imaging for attacks (think of metabolic causes)

• Acute / chronic / hemorrhagic pancreatitis, Dx by raised amylase +/- imaging, known Cx, also in relapses (causes?)

• Strenuous exercise training (offensive body / sweaty feet odor!? Large anion gap metabolic acidosis Vs heat stroke!?)

• Mild phenotype / asymptomatic IVA (932C>T) (A282V) detected by neonatal screening

Misleading presentations in ‘already known’ cases

• Use of pivalate-generating drugs / antibiotics (adefovir dipivoxil, cefteram / cefditoren / cefetamet pivoxil, and pivamicillin, in general NA in TMH, except adefovir) may affect the cutoff value of C5 acyl-carnitine, please interpret the results with chemist / chemical pathologist & check the drugs with pharmacist

• Some pt may withhold Tx thinking that they have been ‘cured’, not telling others / doctors on their previous events, then comatose sometimes later. (Entry to CMS, reminder, drug alert; written / repeated warning to parents & patient)

• Graves’ disease (attack in stably treated IVA case, to Dx Graves’ Ds!?)

Laboratory findings in acute decompensation stage

• Leukothrombocytopenia, anemia, (pancytopenia)• Ketouria• Acidosis with large anion gap• Hypocalcemia, hyperphosphataemia (severely reduced ratio of

phosphocreatine to inorganic phosphate, indicating a major impairment of oxidative phosphorylation), hypomagnesaemia

• Hypo-/hyperglycemia (mistaken as diabeteic ketoacidosis)• Hyperammonaemia• Raised amylase (pancreatitis) • Hyperlactacidemia, hyperuricemia, abnormal LFT,

hypoalbuminemia, hyperargininemia. • Intra-cranial (cerebral / cerebellar) bleeding

• To check CBC, Astrup, ketone bodies, ammonia, amylase, lactate, dried blood spot test, L/RFT, Ca, PO4, Mg, PT, APTT +/- imaging

Remove the toxin

• High dose (IV, but NA in HA!?) carnitine (100-400 mg/kg/day) in 3-4 divided doses, (oral 1 g tds)

• Oral glycine (250-800 mg/kg/day) in 2-4 divided doses (glycine 200 mg/kg every 6 hr can be given rectally if oral intolerance) (also rectal carnitine?)

• Consider dialysis or haemofiltration if for ammonia > 400 – 600μmol/l

• Oral carbamyl-glutamate 50 mg/kg/day in 4 divided doses may also help to reduce the ammonia level.

• Fluid restriction if cerebral edema• Target at no / low leucine metabolites, and normal

serum ammonia levels) (plasma leucine peak 2 hr after leucine loading).

Dialysis!?• For ammonia > 400μmol/l, or persistent > 8 hr • PD / extracorporeal dialysis / continuous hemo-filtration /

hemodialysis [Tx of choice] • Good outcome with pre-dialysis coma duration < 33 hr in

neonates, rather than initial blood ammonium / leucine levels• Cx – severe hypotension / circulatory failure, ischemia of limb after

cannulation of femoral vessels, pulmonary / pericardial hemorrhage, thrombosis, sepsis, rebound, failure to decrease ammonium level).

• Oral N-carbamyl-glutamate (carglumic acid) (NA in HA, not registered in HA, unregistered drug? HK$ 1,083 / 200 mg tablet, a single purchase at least 60 tablets, i.e., HK$ 65,000) (more recent information: another vender, $1,300 / 200 mg tablet, single purchase of 5 tablets, i.e., $6,500, for N-acetylgutamate synthetase def. initial dose 100-200 mg/kg/d, maintenance dose 10-100 mg/kg/d) 50-150 mg/kg/d (up to 250 mg/kg/d) in 4 divided doses can help to reduce the ammonia level, without / avoiding dialysis.

Oral drug to reduce serum ammonium?

• Oral N-carbamyl-glutamate (carglumic acid) 50-150 mg/kg/d (up to 250 mg/kg/d) in 4 divided doses may also help to reduce the ammonia level (effectively used orally in term infant reported) (SE – 13%, vomiting, abdominal pain, pyrexia, tonsillitis, anemia, ear infection, diarrhea, nasopharyngitis, and headache)

• Use of sodium benzoate to increase ammonia detoxication is controversial, benzoic acid with its CoA metabolite competing with isovaleryl-CoA for glycine N-acylase, preventing the beneficial effect of glycine.

Medical emergency – Tx

• Fluid and rehydration• Correct electrolyte disturbance• Treat concomitant sepsis, start empirical

antibiotic (patient likely neutropenic)• Correct bleeding diathesis• Inhibition of endogenous catabolism by

adequate energy supply, and use of leucine free milk formula +/- low dose parenteral nutrition

Caution on Tx!!• Alkalization may cause / exacerbate pre-

existing cerebral edema, and even cerebral hemorrhage (if sodium bicarbonate is to be given, for only 1/4 – 1/2 of the Na requirement, also to avoid precipitation with Ca supplement by Y connector)

• Over-hydration is avoided, rehydration in 48 hours, with fluid infusion < 3 L/m2/day

• Sustained hyperlactacidemia may be due to high glucose infusion, can be reduced by lower glucose infusion.

• Insulin if necessary for hyperglycemia• Protein free diet for not more than 2 days, to

prevent catabolism, to avoid prolonged fasting.

Maintenance drugs

• Oral L-carnitine 25-100 mg/kg/d in 2-3 divided doses, • Oral glycine 40-300 mg/kg/d, for normal metabolite

levels, • Glycine 150-250 mg/kg/d + carnitine 100 mg/kg/d are

recommended. • (Higher glycine may lead to saturation of the glycine

conjugation system & lack of response to metabolic challenge. Glycine > 300 mg/kg/d routinely should be given cautiously. But to increase glycine during relapse / leucine loading.)

• Dried blood spot test / urinary acetyl-carnitine concentration – good marker on optimal dose of L-carnitine supplementation

Glycine supplement dosePR 1988; 24(1): 9-13

PR 1988; 24(1): 9-13PR 1988; 24(1): 9-13

Glycine supplement dosePR 1988; 24(1): 9-13

Caution on drugs (Entry to CMS drug alert)

• Use of aspirin is contraindicated, interfering endogenous detoxifying mechanisms by glycine-N-acylase, similarly for drugs / chemicals containing benzoic acid which prevents the beneficial effect of glycine.

• Use of bupivacaine also be avoided, a case report of malignant ventricular dysrhythmias, even on subcutaneous injection, related to carnitine deficiency and bupivacaine induced cardiotoxicity

• Use of pivalate-generating drugs / antibiotics may affect the cutoff value of C5 acyl-carnitine, please interpret the results with chemist / chemical pathologist

Re-feeding• To avoid chronic endogenous protein catabolism. • Once blood ammonia levels < 150 μmol/L, enteral (tube) feeding / low dose TPN • 50-60% of normal requirement (be aware of leucine content), or a minimum of 0.5 g

protein /kg/d must be added • Counsel dietician, rather than ‘DAT’, because common foods, e.g., rice contains

very high levels of leucine • Switch from parenteral to full enteral nutrition over 4-5 days, daily amount increased

according to blood ammonia levels and leucine (dried blood spot test) levels. • Start with IVA anamix infant (leucine free, trace amount of lactose 69 kcal and 2 g

protein for 100 ml), then add his usual diet. • Restriction of total protein makes little sense as low-leucine medical food is available.

Normal amount of protein can be given. • Self-limited diet, better protein tolerance with increasing age (one pt with normal diet). • Literatures usually reported on low protein diet and high-energy diet, +/- tube feeding,

wide ranges used in literature 0.5-1.5 gm protein /kg/d, 1.2-1.5 g/kg/d for < 7 yr old, up to 1.5-2 g/kg/d

• 800 mg/day leucine a day in infancy, 20-30 g protein/day later, for normal growth and development (1,050 – 1,500 mg leucine /day).

EJCN 2007; 61: 1323-7

EJCN 2007; 61: 1323-7

EJCN 2007; 61: 1323-7

Diet

• Consult dietitian

• Start with leucine free milk formula

• Gradual step up the amount of leucine in diet, to reach minimum requirement of the child’s age and body weight

• No “DAT”

• Normal amount of protein can be given

Cx of diet

• Compliance, feeding problems, anorexia. • Cx of low protein diet – poor growth, low bone

mineral density, low skeletal muscle mass, osteoporosis / osteopenia (acidosis, RTA, lack of sunlight exposure, dietary def., high intake of simple sugars in soft drinks) (Ca + Vit D supplement for prevention), relative protein malnutrition (0.8 – 1 g protein/kg/d), generalized amino acid depletion.

Problems that we may encounter on long-termed follow up

• Growth problem• Developmental delay, mental

retardation, learning difficulties, isolated cognitive impairment, needs of special school

• Movement disorders (tremors, choreoathetosis, dystonia), intermittent ataxia, unsteady gait in teenager

• Generalized hypotonia• Seizures• Abnormal behavior

• Relapse with / without known ppt factor / HPI

• Problem in drug / dietary compliance (patient may stop treatment by himself years later)

• Pancreatitis• Cataract• Some may be normal school,

attending college / university, +/- independent life

• Maternal IVA – good outcomes under supervision reported

Patient support group

• Organic acidemia association: http://www.oaanews.org/

• 罕見疾病基金會 http://www.tfrd.org.tw/rare/typeCont.php?sno=0113&kind_id=

Thanks to the team

• Paediatricians and doctors

• Nurses

• Pathologist

• Microbiologist

• Dietitian

• Speech therapist

• Physiotherapist and occupational therapist