Malignant presternal goitre

Hong Kong Med J 2014;20:156–7 | Number 2, April 2014
DOI: 10.12809/hkmj133946
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Malignant presternal goitre
TL Chow, FRCS (Edin), FHKAM (Surgery)1; Wilson WY Kwan, MRCS1; Joyce YH Hui, FRCR, FHKAM (Radiology)2
1 Department of Surgery, United Christian Hospital, Kwun Tong, Hong Kong
2 Department of Diagnostic Radiology and Organ Imaging, United Christian Hospital, Kwun Tong, Hong Kong
 
Corresponding author: Dr TL Chow (tamlinc@yahoo.com)
Abstract
Goitres usually enlarge and descend caudad into the substernal space and are not palpable. We report on a patient whose goitre spread downward but anterior to the sternum. The thyroid mass was subsequently removed and was proven to be a papillary thyroid carcinoma. The mechanism by which a presternal goitre develops is probably due to invasion and erosion of the strap muscles and the cervical linea alba. The clinical implication of this presentation is complete extirpation of the presternal goitre with a cuff of the strap muscles.
 
 
Introduction
When goitres enlarge, they can extend beyond the boundary of the neck. Since the thyroid gland resides beneath the pretracheal fascia and the strap muscles and their attachments are connected to the top of the manubrium, goitres usually migrate down into the superior mediastinum. Substernal goitres can occur in 8.4% patients undergoing thyroidectomy.1
 
We have treated a patient with a malignant goitre, which spread exceptionally to the presternal region. Herein we report this unusual presentation of an extra-cervical extension of a thyroid mass and stress its association with malignancy.
 
Case report
A 50-year-old man presented to our out-patient clinic in January 2012 with an enlarging anterior neck mass for the past 3 years. He experienced mild pain which prompted him to seek medical advice. A dumb-bell–shaped mass was found over his anterior neck. The upper portion of the mass was about 4.5 cm in diameter and located at the suprasternal region. The lower portion was 3.5 cm in diameter and resided anterior to the sternum, about 3 cm from the upper border of manubrium (Fig 1). The whole mass migrated upward when patient swallowed which signified its thyroid origin.
 

Figure 1. The dumb-bell–shaped thyroid mass is shown. The inferior component extends inferiorly into the subcutaneous area anterior to the sternum
 
Thyroid function test results were normal. Computed tomography 4 weeks later showed an isthmic thyroid mass (3.7 x 2.8 x 3.4 cm) containing micro- and macro-calcifications. The lower component of the dumb-bell–shaped mass was anterior to the sternum (Fig 2), and there was no substernal extension.
 

Figure 2. Pre-contrast, sagittal reformatted computed tomographic image demonstrates that the nodule contains coarse as well as micro-calcifications. The dumb-bell–shaped components of this lesion are marked by asterisks. The lower component was anterior to the sternum
 
The patient was very keen to undergo surgery, but he declined fine-needle aspiration of the mass. Total thyroidectomy with a collar incision was performed 3 weeks later. The 4.5 x 5 cm isthmic thyroid mass passed through the midline fascia (between the strap muscles) and reached the presternal area. The muscle attachments of the strap muscles were at their normal positions on the manubrium. Total thyroidectomy including the entire dumb-bell mass en bloc with surrounding strap muscles and deep fascia was performed.
 
Histopathology revealed papillary thyroid carcinoma in both the superior and inferior components of the dumb-bell mass. The resection margin was clear. Postoperative radioactive iodine ablation 80mCi was given 5 months after the initial presentation (about 10 weeks after surgery). The thyroglobulin level during thyroxine withdrawal was <1.0 μg/L, and there was no evidence of tumour recurrence.
 
Discussion
Substernal goitre is uncommon. Presternal goitre is even rarer. We searched the literature in MEDLINE and came across only two reported cases. The first reported by Raman and Nair2 in 1999 was a papillary thyroid carcinoma. The second described by Brilli et al3 in 2007 was a benign nodular goitre. We report this third case of a presternal goitre, which was also a papillary thyroid carcinoma. Therefore, if a thyroid mass spreads presternally, malignancy should be suspected. In our patient, malignancy was not suspected initially due to little knowledge about presternal goitres at that time. Therefore, an intra-operative frozen section was not obtained. We now realise the high risk of malignancy for this entity, and that preoperative fine-needle aspiration cytology or intra-operative frozen section examination should be performed in all such cases, and better informed consent regarding surgery should be obtained. Moreover, the extent of operation can also be more appropriately determined. In addition, preoperative imaging yielding micro-calcification in the goitre as well as presternal extension, or both should heighten the possibility of an underlying papillary carcinoma.
 
The mechanism resulting in the more common substernal goitre was speculated to the negative intrathoracic pressure during inspiration and the downward pull of gravity.4 By contrast, presternal migration of a malignant thyroid mass (as in our patient) was probably due to tumour erosion of the cervical linea alba between the strap muscles. Prompt investigation with imaging and fine-needle aspiration therefore seems imperative to make an accurate diagnosis and offer early therapy. Such patients should be advised to undergo total thyroidectomy. Notably, the thyroid masses should be removed en bloc with the adjacent strap muscles in order to achieve a clear resection margin.
 
Presternal goitre is rare and likely to represent thyroid malignancy eroding the cervical linea alba and strap muscles. Total thyroidectomy including a cuff of strap muscles encircling the mass should be performed to ensure complete tumour extirpation.
 
References
1. Chow TL, Chan TT, Suen DT, Chu DW, Lam SH. Surgical management of substernal goitre: local experience. Hong Kong Med J 2005;11:360-5.
2. Raman A, Nair A. Presternal extension of a malignant thyroid swelling. Aust N Z J Surg 1999;69:241-2. CrossRef
3. Brilli L, Guarino E, Ghezzi M, Carli AF, Occhini R, Pacini F. Multinodular goiter of unusual shape and location. Thyroid 2007;17:693-4. CrossRef
4. Singh B, Lucente FE, Shaha AR. Substernal goiter: a clinical review. Am J Otolaryngol 1994;15:409-16. CrossRef

Pseudohyperkalaemia with acute leukaemia: association with pneumatic tube transport of blood specimens

Hong Kong Med J 2014;20:158–60 | Number 2, April 2014
DOI: 10.12809/hkmj133881
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Pseudohyperkalaemia with acute leukaemia: association with pneumatic tube transport of blood specimens
Albert SW Ku, FHKAM (Paediatrics), FHKAM (Anaesthesiology); Robin HS Chen, FHKAM (Paediatrics), FHKCPaed; Rocky LK Law, MB, BS
Department of Paediatrics and Adolescent Medicine, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong
 
Corresponding author: Dr ASW Ku (alku1298@hkstar.com)
Abstract
Falsely elevated serum or plasma potassium level can be the result of mechanical injury to blood cells. We describe pseudohyperkalaemia caused by pneumatic tube transport of blood specimens from a patient with leukaemia. Clinicians should be aware of this possibility when interpreting the clinical significance of hyperkalaemia. In leukaemic patients, pneumatic tube transport of blood specimens for potassium analysis should be avoided.
 
 
Case report
A 10-year-old boy was referred from another hospital for malaise and on-and-off fever for 2 weeks in August 2010. There were no respiratory, urinary, gastro-intestinal, or neurological symptoms. Physical examination revealed a febrile child with pallor. There were multiple bruises over the lower limbs, multiple cervical and inguinal lymph nodes, and hepatosplenomegaly. The potassium level checked in the referring hospital was 4.3 mmol/L.
 
Laboratory investigations in our hospital revealed a white blood cell (WBC) count of 340.6 x 109 /L with blast cell count of 282.69 x 109 /L (83%). The neutrophil count was 45.41 x 109 /L (13.3%), with 1.14 x 109 /L (0.3%) metamyelocytes. The haemoglobin level was 71 g/L and platelet count was 68 x 109 /L. Blood biochemistry revealed the following serum levels: potassium 6.0 mmol/L, sodium 137 mmol/L, urea 5.0 mmol/L, creatinine 61 μmol/L, calcium 2.33 mmol/L, phosphate 1.38 mmol/L, urate 0.4 mmol/L, and the serum lactate dehydrogenase concentration was 3800 IU/L. The potassium assay was repeated with blood specimen drawn from a venepuncture into a serum specimen bottle. The result was 7.4 mmol/L. It was suspected to be a factitious result related to clotting of the specimen or haemolysis. Another venous sample was collected into a heparinised bottle for plasma potassium level assay and was sent to laboratory by pneumatic tube for urgent analysis. The result was 8.2 mmol/L.
 
In view of the rapidly rising potassium level in a patient at risk of tumour lysis syndrome, despite cytotoxic chemotherapy not having been commenced, the patient was transferred to the paediatric intensive care unit. Electrocardiography revealed a sinus tachycardia of 125 beats/min with no features to suggest hyperkalaemic change. An arterial specimen drawn from an arterial line into a heparinised bottle was sent to the laboratory by special messenger. Treatment of hyperkalaemia was commenced before availability of the result in view of the perceived rapidly rising potassium level from 6.0 mmol/L to 8.2 mmol/L in less than 5 hours. He was given a dose of calcium gluconate, insulin with dextrose, and a dose of calcium polystyrene sulphonate resin. Hyperhydration with intravenous fluid 2.5 L/m2/day together with allopurinol, ceftazidime and amikacin were also commenced. The plasma potassium level in the pre-treatment arterial specimen was 4.2 mmol/L.
 
Potassium level was measured again after dextrose-insulin using an arterial heparinised sample. The specimen was sent to laboratory by pneumatic tube for urgent analysis. The result was 9.2 mmol/L, which was suspected to be factitious. Therefore paired serum and plasma specimens were sent to the laboratory by special messenger for careful, urgent processing. The resulting plasma potassium level was 4.1 mmol/L and the serum sample showed interference from potassium leakage. As the condition of pseudohyperkalaemia became evident, no further therapy for hyperkalaemia was given. The patient was then transferred to a paediatric oncology centre, where the diagnosis of acute T-cell lymphoblastic leukaemia was confirmed. His electrocardiogram and blood glucose level were normal all along; the plasma potassium level checked before transfer was 4.6 mmol/L. The Table shows a summary of serum and plasma potassium level results with reference to the sampling time after hospital admission and processing techniques. Arterial line samples drawn into heparinised bottles with delivery by messenger showed more reliable and consistent results.
 

Table. Potassium results of specimens handled by different methods
 
Discussion
Hyperkalaemia is a potentially life-threatening condition for which emergency treatment may be necessary. However, pseudohyperkalaemia is a common laboratory artefact and, if unrecognised, may lead to a dilemma.1 2 Workup for falsely elevated potassium levels may lead to delay in treatment and waste of resources. On the other hand, aggressive treatment including renal dialysis may be unnecessarily commenced.3 Therefore, clinicians should be aware of the conditions that may give rise to falsely elevated potassium levels.
 
In most cases, pseudohyperkalaemia occurs during the collection process, transport, or storage of specimens.4 The artefact is due to leaching of potassium from cytosols during clotting or storage of the sample.1 Leakage of potassium from blood cells can occur as an in-vitro phenomenon during blood coagulation.5 6 7 This phenomenon is usually encountered in serum and not plasma. Serum potassium levels have been reported to be higher than plasma levels, with a mean difference of 0.36 ± 0.18 mmol/L in samples with a normal number of blood cells.8 Therefore anticoagulated plasma samples provide more accurate measurement of the true potassium level.1 Lithium heparin is the recommended anticoagulant for this purpose.4
 
Potassium release from red blood cells by in-vitro haemolysis is a well-recognised cause of spurious results. Conditions that induce in-vitro haemolysis include fist clenching during phlebotomy, drawing blood into an evacuated tube, use of small-gauge needles, use of tourniquets, cold storage, delay in sample processing, mechanical trauma during vigorous mixing, or hard centrifugation.1 3 There is a rare genetic condition, familial pseudohyperkalaemia, which is an autosomal dominant disorder associated with excessive leakage of potassium across red cell membranes.9
 
Pseudohyperkalaemia can also be the result of pre-existing pathological conditions resulting in cellular potassium leakage. Such conditions include acute leukaemia, chronic myeloproliferative disorders (chronic myeloid leukaemia, polycythaemia vera, essential thrombocythaemia), chronic lymphocytic leukaemia, and reactive thrombocytosis.1 10 The large number of blood cells may exaggerate the effects of potassium leakage from coagulation and further increase the discrepancy between serum and plasma potassium levels. Unphysiological conditions and shortage of metabolic fuels leading to impaired sodium/potassium adenosine triphosphatase activity may contribute to release of potassium from large numbers of white cells.7 The abnormal fragility of malignant leukocytes also makes them susceptible to mechanical stress. Colussi11 reported that the minor mechanical stress of drawing blood into vacuum tubes or syringe shaking induced lysis of leukaemic lymphocytes that appeared in blood smears as lymphocytic ghosts called “basket cells”. Kellerman and Thornbery3 reported the occurrence of pseudohyperkalaemia due to pneumatic tube transport in a leukaemic patient with a WBC count of 290 x 109 /L, but they did not find any significant differences in potassium values between walked and tube-transported specimens in control patients with normal WBC counts. The effect on potassium resulting from pneumatic tube transport is likely due to both WBC number and fragility.3 Chawla et al12 also reported a case of pseudohyperkalaemia due to mechanical disruption of leukocytes in a patient with chronic lymphocytic leukaemia and proposed to designate this phenomenon as pneumatic tube “pseudo tumour lysis syndrome”. Ruddy et al13 also reported a chronic lymphocytic leukaemia patient with venous potassium levels spuriously higher than arterial potassium levels. The authors hypothesised that this was likely due to a greater opportunity for lysis of white blood cells in the venous blood related to differences in mechanical stressors between venous and arterial blood draw techniques.13 In our patient, the possible contributing factors for pseudohyperkalaemia include high WBC count, fragile leukaemic blast cells, clotting of serum specimens, and mechanical trauma secondary to pneumatic tube transport.
 
Pseudohyperkalaemia is characterised by an elevation of serum potassium levels in the absence of clinical evidence of electrolyte imbalance,10 and should be suspected when there are no other clinical features of hyperkalaemia, such as peaked T waves and QRS widening on the electrocardiogram.3 The potassium level should therefore be interpreted together with the clinical context and other investigation results. Hyperkalaemia is exceptionally unlikely if renal indices are normal and there are no predisposing factors, such as intake of potassium supplements and/or drugs that raise potassium levels.4 In our patient, the possibility of a spurious result was suspected at an early stage. Treatment was commenced because potassium levels showed a rising trend in a patient at risk of tumour lysis syndrome. Ultimately, the pseudohyperkalaemia was confirmed by elimination of the possible causes of measurement error. In this patient, there were hints to remind clinicians to consider the possibility of factitious results as the electrocardiogram was normal all along and the other expected biochemical changes of tumour lysis syndrome were absent.
 
Besides pseudohyperkalaemia, factitious hypokalaemia may also be encountered in patients with leukaemia with WBC counts higher than 100 x 109 /L when blood samples are allowed to stand at room temperature.1 This phenomenon is related to transcellular potassium shift into leukaemic cells.1 Even in normal specimens, pseudohypokalaemia may also be noted if sample analysis is delayed, and is believed to be mediated by sodium-potassium-exchanging ATPase,14 while specimen deterioration due to long storage can lead to pseudohyperkalaemia.4
 
In conclusion, when considering investigation and treatment, clinicians should be aware of the potential causes of pseudohyperkalaemia in leukaemic patients. Extreme care in handling blood samples is very important. The use of pneumatic tube transport for potassium analysis should be avoided in leukaemic patients.
 
References
1. Dalal BI, Brigden ML. Factitious biochemical measurements resulting from haematologic conditions. Am J Clin Pathol 2009;131:195-204. CrossRef
2. Brigden ML, Dalal BI. Spurious and artifactual test results, II: morphologic abnormalities, pseudosyndromes and spurious test results. Lab Med 1999;30:397-405.
3. Kellerman PS, Thornbery JM. Pseudohyperkalaemia due to pneumatic tube transport in a leukaemic patient. Am J Kidney Dis 2005;46:746-8. CrossRef
4. Smellie WS. Spurious hyperkalaemia. BMJ 2007;334:693-5. CrossRef
5. Hartmann RC, Auditore JV, Jackson DP. Studies on thrombocytosis. Hyperkalaemia due to release of potassium from platelet during coagulation. J Clin Invest 1958;37:699-707. CrossRef
6. Bronson WR, DeVita VT, Carbone PP, Cotlove E. Pseudohyperkalaemia due to release of potassium from white blood cells during clotting. N Engl J Med 1966;274:369-75. CrossRef
7. Colussi G, Cipriani D. Pseudohyperkalaemia in extreme leukocytosis. Am J Nephrol 1995;15:450-2. CrossRef
8. Nijsten MW, de Smet BJ, Dofferhoff AS. Pseudohyperkalemia and platelet counts. N Engl J Med 1991;325:1107. CrossRef
9. Iolascon A, Stewart GW, Ajetunmobi JF, et al. Familial pseudohyperkalaemia maps to the same locus as dehydration hereditary stomatocytosis (hereditary xerocytosis). Blood 1999;93:3120-3.
10. Sevastos N, Theodossiades G, Efstathiou S, Papatheodoridis GV, Manesis E, Archimandritis AJ. Pseudohyperkalaemia in serum: the phenomenon and its clinical magnitude. J Lab Clin Med 2006;147:139-44. CrossRef
11. Colussi G. Pseudohyperkalaemia in leukaemias. Am J Kidney Dis 2006;47:373. CrossRef
12. Chawla NR, Shapiro J, Sham RL. Pneumatic tube "pseudo tumour lysis syndrome" in chronic lymphocytic leukaemia. Am J Hematol 2009;84:613-4. CrossRef
13. Ruddy KJ, Wu D, Brown JR. Pseudohyperkalaemia in chronic lymphocytic leukaemia. J Clin Oncol 2008;26:2781-2. CrossRef
14. Sodi R, Davison AS, Holmes E, Hine TJ, Roberts NB. The phenomenon of seasonal pseudohypokalemia: effects of ambient temperature, plasma glucose and role for sodium-potassium-exchanging-ATPase. Clin Biochem 2009;42:813-8. CrossRef

A rare cause of severe diarrhoea diagnosed by urine metabolic screening: aromatic L-amino acid decarboxylase deficiency

Hong Kong Med J 2014;20:161–4 | Number 2, April 2014
DOI: 10.12809/hkmj133922
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
A rare cause of severe diarrhoea diagnosed by urine metabolic screening: aromatic L-amino acid decarboxylase deficiency
LK Lee, MB, BS, MRCPCH1; KM Cheung, MB, ChB, FHKAM (Paediatrics)1; WW Cheng, MB, ChB, FHKAM (Paediatrics)1; CH Ko, FRCP, RCPS (Glasg)1; Hencher HC Lee, FHKCPath, FRCPA2; CK Ching, FRCPA, FHKAM (Pathology)2; Chloe M Mak, FHKCPath, FHKAM (Pathology)2
1 Department of Paediatrics and Adolescent Medicine, Caritas Medical Centre, Shamshuipo, Hong Kong
2 Chemical Pathology Laboratory, Department of Pathology, Princess Margaret Hospital, Laichikok, Hong Kong
 
Corresponding author: Dr LK Lee (samantha_1703@hotmail.com)
Abstract
A 15-year-old Chinese male with infantile-onset hypotonia, developmental delay, ptosis, and oculogyric episodes presented with a history of chronic diarrhoea since the age of 5 years. At presentation, he had an exacerbation of diarrhoeal symptoms resulting in dehydration and malnutrition with a concurrent severe chest infection. In view of his infantile-onset hypotonia, oculogyric crises, and protracted diarrhoea, an autonomic disturbance related to neurotransmitters was suspected. Urine organic acid profiling was compatible with aromatic L-amino acid decarboxylase deficiency. The diagnosis was confirmed based on cerebrospinal fluid analysis and genetic mutation analysis. The patient was treated with a combination of bromocriptine, selegiline, and pyridoxine; a satisfactory reduction in diarrhoea ensued. Our report highlights the importance of urine organic acid screening in infantile-onset hypotonia, especially when accompanied by oculogyric crises, and severe diarrhoea which could manifest as a result of autonomic disturbance.
 
 
 
Case report
A 15-year-old Chinese male, with neurological impairment and a history of chronic diarrhoea, presented with intractable diarrhoea after an episode of severe pneumonia with a pleural effusion that eventually resolved after 8 weeks of antibiotic therapy. The chronic watery diarrhoea (averaging 7 motions/day) persisted despite cessation of antibiotics for 1 month. His body weight had dropped from 26.6 kg to 21.7 kg. Hydration and electrolyte balance was maintained by 1.7 L/day of lactose-and-sucrose-free elemental formula and intravenous fluid, supplemented by potassium (1.8 mmol/kg/ day). Serial infection screens for rotavirus, norovirus, bacterial culture, ova, cysts, and Clostridium difficile toxin were negative. Blood tests yielded a reduced plasma albumin level (24 g/L; reference range, 37-47 g/L), but the blood lymphocyte count (2 x 109 /L) and immunoglobulin levels (IgG 1980 mg/dL, IgA 447 mg/dL, IgM 111 mg/dL) were normal. Intravenous octreotide (mimics somatostatin) up to 200 μg per day was given for 1 week with a view to easing his diarrhoea,1 but no obvious benefit ensued.
 
On reviewing the history, the patient had global developmental delay and truncal hypotonia since the age of 8 months. He became bed-bound aged 1.5 years and also had a history of recurrent aspiration pneumonia since early childhood. His recurrent pneumonia became worse in 2008 (aged 11-12 years). After a gastrostomy and fundoplication when he was 13 years old, his condition improved partially, but he still endured two to three episodes of pneumonia every year. At the age of 15 years he had an episode of pneumonia associated with a pleural effusion, which was by far the most severe since his gastrostomy and fundoplication. Bilateral ptosis had been noted when he was 3.5 years old, and brief episodes of up-rolling eyeballs were reported since the age of 4 years. The electroencephalogram showed sharp waves over both hemispheres, especially over both temporal and the left centro-temporal areas. The patient was treated with carbamazepine, but there was minimal improvement of his abnormal eye movements. Metabolic workup, including thyroid function tests, and determination of ammonia, lactate, and glucose levels and urine amino acids screening yielded nil abnormal. Magnetic resonance imaging of the brain, muscle biopsy, sural nerve biopsy, the Tensilon test, hearing and ophthalmological screening were all unremarkable. Genetic studies excluded spinal muscular atrophy, myotonic dystrophy, and Fragile X syndrome. At the age of 5 years, he started having chronic watery diarrhoea, which occurred after each episode of aspiration pneumonia with respiratory failure. Stool microscopy showed one white cell per high power field, yielded no fat globules, ova, or cysts. Clostridium difficile cytotoxin and stool cultures were negative. Stool-reducing substance was undetectable. Serum cortisol was normal. Four months after a trial of semi-elemental and elemental formula and the use of anti-diarrhoeal medication, there was some improvement of his diarrhoea. The patient’s body weight remained at the third percentile with a fluid intake of approximately 1.3 L/day, and at that time his diarrhoea was regarded as functional.
 
The patient was transferred to our unit at the age of 6 years. Aged 9 years, he had an unexplained witnessed cardiac arrest in the Developmental Disabilities Unit of the Caritas Medical Centre, which was confirmed to be asystolic. Consequently, the patient suffered permanent neurological damage. When he was 11 years old, there was an episode of protracted hypotension with bradycardia (for 5 hours), which followed sedation (with diazepam 0.1 mg/kg) for an oesophagogastroduodenoscopy. Aged 13 years, he had an exacerbation of severe watery diarrhoea after undergoing laparoscopic fundoplication and gastrostomy, which was followed by marked weight loss (3.9 kg) over 1 month. There was no steatorrhoea; the patient’s lipid profile was normal and stool cultures were again negative. The diarrhoea ameliorated after he started feeding with semi-elemental prebiotic formulas, as well as treatment with diphenoxylate and atropine. He regained his body weight reaching 26.6 kg over the subsequent year. The entire episode was attributed to postoperative dumping syndrome.
 
In view of the multisystem involvement, urine metabolic profiling was performed. This showed hyper-excretion of vanillactate, 3-O-methyl-DOPA and N-acetyl-vanilalanine with hypo-excretions of 5-hydroxyindoleacetic acid (5-HIAA) and vanillylmandelic acid. The result was compatible with aromatic L-amino acid decarboxylase (AADC) deficiency. The diagnosis was confirmed by cerebrospinal fluid examination, which showed a marked increase in 3-O-methyl-DOPA (365 nmol/L) and 5-hydroxytryptophan (72 nmol/L), with undetectable 5-HIAA (<5 nmol/L) and homovanillic acid (<5 nmol/L). Mutation analysis of the DOPA decarboxylase (DDC) gene revealed a heterozygous c.714+4A>T and c.1312T>C (p.Cys438Arg) mutation. This particular mutation NM_000790.3(DDC):c.714+4A>T was known to cause AADC deficiency and was by far the most common mutation causing this condition in the Chinese.2 The patient was given a combination of bromocriptine 2.5 mg twice a day, selegiline 5 mg daily, and vitamin B6 200 mg twice daily for the next 6 months and appeared to have a good response, as inferred by the reduced frequency of diarrhoeal episodes (2-3 times/day), weight gain to 27.7 kg (at latest follow-up), and diminished recourse to potassium supplementation (0.7 mmol/kg/day). He also became more tolerant of higher milk-drip rates (from 50 to 300 mL/h) and volume of fluid intake (1.5 L/day). He has had no recurrences of severe diarrhoea accompanying subsequent illness episodes.
 
Discussion
Deficiency of AADC is a rare metabolic disorder; worldwide, less than 100 patients have been reported.3 The patient commonly presented at the age of less than 1 year, with developmental delay, dystonia, and autonomic dysfunction. Diarrhoea was reported in 50% of the patients in one Taiwan series,4 however, severe diarrhoea was seldom reported. This case report highlights the importance of a high index of suspicion for neurotransmitter disease in infantile-onset hypotonia with extrapyramidal features, and shows that severe diarrhoea can be the predominant feature of an autonomic disturbance.
 
Since AADC is an important enzyme in monoamine biosynthesis (Fig), if lacking it results in dopamine and norepinephrine deficiency. Norepinephrine deficiency results in unopposed acetylcholine activity, leading to increased intestinal motility and relaxation of sphincters. The resultant reduction in intestinal transit time may impair absorption. Moreover, unopposed acetylcholine activity stimulates intestinal secretion, which also contributes to diarrhoea.5 A shorter transit time in the distal small bowel has also been reported in diabetic patients with autonomic dysfunction.6 7 The rapid passage of chyme into the large bowel results in impaired water and electrolyte absorption and hence diarrhoea, for which a defect in alpha-adrenergic activity is thought to play a key pathological role.6 7 The autonomic features present in our patient (bilateral ptosis, and protracted periods of hypotension with bradycardia) are also compatible with AADC deficiency. Moreover, the unexplained cardiac arrest could have been due to unopposed vagal tone; evidently, in AADC deficiency a stress as minor as catheter insertion can result in severe bradycardia and cardiac arrest.8 Autonomic dysfunction was prominent in our patient, and potentially could account for the severe diarrhoea.
 

Figure. Pathway of monoamines synthesis
 
In the literature, patients have been diagnosed during infancy or early childhood owing to movement disorders or autonomic features, including truncal hypotonia, hyper-reflexia, oculogyric crises, ptosis, sweating, nasal congestion, and labile blood pressures and heart rates. Owing to a reduced lifespan, clinical features in late childhood are rarely reported. The presentation with chronic diarrhoea punctuated by episodic exacerbations of dehydration and malabsorption with superadded neurological impairment may result in the characteristic clinical features of AADC deficiency in the late childhood. Although the diarrhoea in our patient responded favourably to the combination of dopamine receptor agonist, monoamine, oxidase inhibitor and pyridoxine (the cofactor for AADC), no improvement in cognitive or motor function was observed. According to the literature, the clinical efficacy of dopamine agonists, monoamine oxidase inhibitors, AADC cofactors (pyridoxine and pyridoxal phosphate [PLP]), and anticholinergics remains variable.2 Commonly used dopamine agonists aimed at improving motor deficits include bromocriptine and pergolide. Selegiline has been reported to improve oculogyric crises, muscle tone and strength, gastro-intestinal function, hypersalivation and sleep patterns, but according to some reports such effects were transient.9 Pyridoxine (usual dosage of 100-400 mg/day) was commonly added to the treatment with the aim of boosting AADC activity through cofactor excess, but has not been reported to significantly improve clinical outcomes. The use of pyridoxine 145 mg/kg/day had been reported, but has resulted in significant gastro-intestinal side-effects that warranted dose reduction.9 There was evidence that PLP, the active metabolite of pyridoxine, was important for AADC stability. It was postulated that the direct enteral administration of this compound could be dephosphorylated by intestinal phosphatases, absorbed into the bloodstream, and cross the blood-brain barrier. Conceivably, this could provide a more efficient supply of PLP to the brain than pyridoxine (that requires multiple metabolic steps).9 10 However, the necessary efficacious dose has not been established9 and clinical outcomes still remain unclear. At the moment, even with early diagnosis, the overall prognosis of patients with AADC deficiency remains guarded, particularly in terms of neurological outcomes and autonomic disturbance.2
 
References
1. Farthing MJ. Octreotide in the treatment of refractory diarrhoea and intestinal fistula. Gut 1994;35(3 Suppl):S5-10. CrossRef
2. Brun L, Ngu LH, Keng WT, et al. Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency. Neurology 2010;75:64-71. CrossRef
3. Lee HC, Lai CK, Yau KC, et al. Non-invasive urinary screening for aromatic L-amino acid decarboxylase deficiency in high-prevalence areas: a pilot study. Clinica Chimica Acta 2012;413:126-30. CrossRef
4. Lee NC, Shieh YD, Chien YH, et al. Aromatic L-amino acid decarboxylase deficiency in Taiwan. Eur J Paediatr Neurol 2009;13:135-40. CrossRef
5. Ganong WF. Review of medical physiology. 20th ed. New York: Lange; 2001.
6. Rosa-e-Silva L, Troncon LE, Oliveira RB, Foss MC, Braga FJ, Gallo Júnior L. Rapid distal small bowel transit associated with sympathetic denervation in type I diabetes mellitus. Gut 1996;39:748-56. CrossRef
7. Chang EB, Bergenstal RM, Field M. Diarrhea in streptozocin-treated rats. Loss of adrenergic regulation of intestinal fluid and electrolyte transport. J Clin Invest 1985;75:1666-70. CrossRef
8. Swoboda KJ, Saul JP, McKenna CE, Speller NB, Hyland K. Aromatic L-amino acid decarboxylase deficiency: overview of clinical features and outcomes. Ann Neurol 2003;54 Suppl 6:S49-55. CrossRef
9. Allen GF, Land JM, Heales SJ. A new perspective on the treatment of aromatic L-amino acid decarboxylase deficiency. Mol Genet Metab 2009;97:6-14. CrossRef
10. Clayton PT. B6-responsive disorders: a model of vitamin dependency. J Inherit Metab Dis 2006;29:317-26. CrossRef

Atypical focal cortical dysplasia in a patient with Cowden syndrome

Hong Kong Med J 2014;20:165–7 | Number 2, April 2014
DOI: 10.12809/hkmj133863
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Atypical focal cortical dysplasia in a patient with Cowden syndrome
KM Cheung, MB, ChB1; CW Lam, MB, ChB, PhD4; YK Chan, MB, BS2; WK Siu, MB, BS5; L Yong, MB, ChB3
1 Department of Paediatrics, Caritas Medical Centre, Shamshuipo, Hong Kong
2 Department of Medicine and Geriatrics, Caritas Medical Centre, Shamshuipo, Hong Kong
3 Department of Surgery, Caritas Medical Centre, Shamshuipo, Hong Kong
4 Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong
5 Kowloon West Cluster Laboratory Genetic Service, Chemical Pathology Laboratory, Department of Pathology, Princess Margaret Hospital, Laichikok, Hong Kong
 
Corresponding author: Dr KM Cheung (jennykmcheung@gmail.com)
 
Abstract
A macrocephalic girl presented with generalised epilepsy due to focal cortical dysplasia. She later developed multiple hamartomatous lesions and was diagnosed to have Cowden syndrome. The diagnosis was confirmed by identification of a novel frameshift mutation in the PTEN gene of the patient.
 
 
Case report
A 10-year-old Chinese girl presented to a paediatric clinic with epilepsy. She had normal intelligence and social interaction ability, and no relevant family history. She had been having recurrent sleep seizures, with generalised twitching of all four limbs, cyanosis, up-rolling of eyeballs, drooling, and urinary incontinence. Her head circumference was 61 cm (5 cm > the 97th percentile). Physical examination was otherwise normal. The electroencephalogram showed an abnormal focus at the right temporo-occipital region. Goldmann perimetry revealed no abnormality. Magnetic resonance imaging (MRI) with contrast showed pachygyria (total loss of sulcation) with hyperplastic white matter and disorganisation of the grey and white matters in the right occipital lobe. A 2.5 cm x 1.8 cm T2 hyperintense area around the right occipital horn was consistent with gliosis. The right occipital lobe was mildly enlarged. Repeated MRI 5 and 7 years after presentation showed no interval changes. Her findings were compatible with focal cortical dysplasia involving the right occipital lobe (Fig 1). The epilepsy was under good control with carbamazepine treatment. She developed a goitre at the age of 16 years, but was euthyroid and ultrasonography showed a multinodular goitre. Hypertrichosis was noted when she was 17 years old. Multiple tiny papules were noted at the perinasal region, of which the patient regarded as coarse skin. At the age of 19 years, she was incidentally found to have iron deficiency anaemia (haemoglobin 96 g/L [reference range, 117-149 g/L], mean corpuscular volume 68.5 fL [82-97 fL], serum iron 2 μmol/L [5.0-30.4 μmol/L], total iron binding capacity 77.1 μmol/L [44.8-76.0 μmol/L]). She had no gastro-intestinal symptoms, but did receive iron supplements.
 

Figure 1. Magnetic resonance imaging flare sequence showing focal cortical dysplasia at right occipital lobe
 
She had a left hemithyroidectomy at the age of 22 years for increasing size of a dominant left-sided thyroid nodule that expanded from 1.7 × 1.4 × 0.8 cm to 3.6 × 2.9 × 4.2 cm over 10 months. Fine-needle aspiration showed lymphocytic thyroiditis, and excisional biopsy revealed adenomatous hyperplasia. At the age of 23 years, enlargement of a thyroid nodule in the right thyroid lobe (3 cm in diameter) was noted; fine-needle aspiration suggested it was an adenomatous nodule. Total thyroidectomy was performed, and excisional biopsy revealed an atypical nodule with atypical enlarged vesicular nuclei and small distinct nucleoli. The patient also developed a 3-cm scalp papilloma, shown by excisional biopsy to be fibrous papule. At the age of 24 years, she also experienced coffee ground vomiting; oesophagogastroduodenoscopy showed diffuse glycogen deposits at the lower oesophagus and multiple gastric polyps. Polypectomy yielded lymphoid hyperplasia, and oesophageal mucosa biopsy was reported as showing glycogenic acanthosis.
 
In view of her multiple benign tumours, the possibility of a hamartomatous polyposis syndrome was suspected. Subsequent clinical examination yielded multiple papillomas over the face and tongue, but there was no pigmentation of the lips. These mucocutaneous features were pathognomonic criteria of Cowden syndrome. Notably, macrocephaly, thyroid adenoma, gastro-intestinal hamartomas (oesophageal glycogenic acanthosis and gastric polyps), and skin fibromas fulfilled one major and three minor clinical criteria of Cowden syndrome. Mutational analysis of the PTEN gene (Fig 2) showed a heterozygous thymine deletion in exon 8 at position 1023 (NM_000314.4(PTEN_ v001):c.1023del). This deletion creates a frame shift starting at codon Phe341. The new reading frame ends in a stop codon 2 position downstream (NM_000314.4(PTEN_i001):p.(Phe341Leufs*3). This mutation was not detected in the mother. The patient’s father was deceased 10 years earlier due to lung cancer, but he did not have macrocephaly or a history of any other tumours.
 

Figure 2. Mutational analysis for patient with Cowden syndrome
 
Discussion
Cowden syndrome was first described by Lloyd and Dennis in 1963.1 It is characterised by macrocephaly, mucocutaneous lesions, acral (extremity/limb) keratosis, papillomatous papules, and high risk of development of cancer in the breast, thyroid, and endometrium. It is a rare autosomal dominant disease, with an estimated prevalence of 1 in 1 000 000 to 250 000 based on genetic identification.2 Lesions can occur in tissues derived from all three embryonic germ cell layers. The subtle and variable clinical manifestations contribute to the difficulty in making a clinical diagnosis. In 1996, the international Cowden Consortium identified germline PTEN (phosphatase and tensin homologue on chromosome 10) mutations as a cause of Cowden syndrome.2 This is a tumour suppressor gene encoding a major lipid phosphatase that functions in the phosphoinositide 3-kinase signalling cascade.3 It regulates cellular processes crucial for normal development, including cell proliferation, soma growth, cell death, and cell migration.4 The importance on PTEN mutations in making a diagnosis, genetic counselling, and clinical surveillance for the development of malignancies is well recognised. Apart from cancer susceptibility, the PTEN mutation was also implicated as candidate gene in developmental disorder like autism and mental retardation.4
 
Our patient was first suspected to have Cowden syndrome because of the interesting endoscopic findings, as multiple gastric polyps are rarely encountered in young adults. Patients with such polyps should be examined for various genetic syndromes associated with gastro-intestinal polyps, including Peutz-Jeghers syndrome, Cowden syndrome, and Cronkhite-Canada syndrome.5 Histology shows Helicobacter pylori–negative, non-specific lymphoid hyperplasia. Diffuse oesophageal glycogenic acanthosis has seldom been seen in young adults. The concurrence of oesophageal glycogenic acanthosis and multiple gastric polyps is associated with Cowden syndrome.6 7 8
 
Adult-onset Lhermitte-Duclos disease (LDD), which presents clinically with progressive cerebellar sign and increased intracranial pressure, is also a feature. A dysplastic cerebellar gangliocytoma is now considered to be one of the central nervous system (CNS) pathognomonic criteria by the revised Cowden Syndrome Consortium. The other overt CNS manifestations of Cowden syndrome included macrocephaly, autism, developmental delay, brain tumour, and LDD. The unique feature in our patient was the presentation with generalised epilepsy in childhood and the identification of focal cortical dysplasia in the right occipital region. To our knowledge, such brain MRI imaging has not been described previously in Cowden syndrome.9 Apart from regulating cell growth, the PTEN gene also plays a role in cell migration. It interacts with focal adhesion kinase, which results in the inhibition of cell migration and spread. Focal cortical dysplasia is a kind of neuronal migration disorder. Our patient was noted to have a right occipital focal cortical dysplasia and right megalencephaly. These features suggest CNS manifestations of the PTEN mutation. Inclusion of this feature in Cowden syndrome may facilitate early diagnosis.
 
Cowden syndrome represents a late-onset phenotype of the PTEN mutation. Early presentation of PTEN mutations include Bannayan-Riley-Ruvalcaba syndrome and autism spectrum disorder with macrocephaly. Bannayan-Riley-Ruvalcaba syndrome is a congenital disorder characterised by macrocephaly, hamartomatous intestinal polyps, lipomas, and pigmented macules on the penis. To our knowledge, our patient represents a new PTEN mutation phenotype, with macrocephaly and focal cortical dysplasia at the occipital region and subsequent full-blown presentation of Cowden syndrome.
 
In conclusion, we believe we have identified a new phenotype of Cowden syndrome and a new PTEN indel mutation. This PTEN mutation appears to cause megalencephaly, epilepsy, focal cortical dysplasia in the occipital region in childhood, and multiple hamartomatous lesions in late adolescence and early adulthood. The inclusion of focal cortical dysplasia in the occipital region as a CNS feature of the PTEN mutation could facilitate early diagnosis of PTEN mutation syndromes, and clinicians to undertake early surveillance for possible malignancies. In the latest published prospective study of the Ohio cohort of patients with germline PTEN mutation, the penetrance of breast cancer was found to begin at around the age of 30 years rising to an estimated 85% lifetime risk.10 The lifetime risk of breast cancer in females with PTEN mutations was even higher than the best estimates for individuals with BRCA1 or BRCA2 mutations.11 The PTEN-related endometrial cancer risk begins at the age of 25 years rising to 30% by the age of 60 years.10 The thyroid cancer risk begins at birth and continues lifelong.10 Risks of colorectal and kidney cancers begin at around the age of 40 years, with a lifetime risk of 9% and 34%, respectively.10 The earliest reported age of onset of melanoma was in a 3-year-old patient.10
 
References
1. Lloyd KM 2nd, Dennis M. Cowden's disease. A possible new symptom complex with multiple system involvement. Ann Intern Med 1963;58:136-42. CrossRef
2. Farooq A, Walker LJ, Bowling J, Audisio RA. Cowden syndrome. Cancer Treat Rev 2010;36:577-83. CrossRef
3. Shen WH, Balajee AS, Wang J, et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 2007;128:157-70. CrossRef
4. Orrico A, Galli L, Buoni S, Orsi A, Vonella G, Sorrentino V. Novel PTEN mutations in neurodevelopmental disorders and macrocephaly. Clin Genet 2009;75:195-8. CrossRef
5. Hizawa K, Iida M, Matsumoto T, et al. Gastrointestinal manifestations of Cowden's disease. Report of four cases. J Clin Gastroenterol 1994;18:13-8. CrossRef
6. McGarrity TJ, Wagner Baker MJ, Ruggiero FM, et al. GI polyposis and glycogenic acanthosis of the esophagus associated with PTEN mutation positive Cowden syndrome in the absence of cutaneous manifestations. Am J Gastroenterol 2003;98:1429-34. CrossRef
7. Vasovcak P, Krepelova A, Puchmajerova A, et al. A novel mutation of PTEN gene in a patient with Cowden syndrome with excessive papillomatosis of the lips, discrete cutaneous lesions, and gastrointestinal polyposis. Eur J Gastroenterol Hepatol 2007;19:513-7. CrossRef
8. Ha M, Chung JW, Hahm KB, et al. A case of Cowden syndrome diagnosed from multiple gastric polyposis. World J Gastroenterol 2012;18:861-4. CrossRef
9. Lok, C, Viseux V, Avril MF, et al. Brain magnetic resonance imaging in patients with Cowden syndrome. Medicine (Baltimore) 2005;84:129-36. CrossRef
10. Tan MH, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res 2012;18:400-7. CrossRef
11. Metcalfe K, Lubinski J, Lynch HT, et al. Family history of cancer and cancer risks in women with BRCA1 or BRCA2 mutations. J Natl Cancer Inst 2010;102:1874-8. CrossRef

Middle cerebral artery infarction in a cancer patient: a fatal case of Trousseau’s syndrome

Hong Kong Med J 2014;20:74–7 | Number 1, February 2014
DOI: 10.12809/hkmj133780
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Middle cerebral artery infarction in a cancer patient: a fatal case of Trousseau’s syndrome
Peter YM Woo, MB, BS, MRCS (Edin)1; Danny TM Chan, MB, ChB, FRCS (Edin)1; Tom CY Cheung, MB, ChB, FRCR2; XL Zhu, BMed (Jinan) FRCS (Edin)1; WS Poon, MB, ChB (Glasg), FRCS (Edin)1
1 Division of Neurosurgery, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
2 Department of Imaging and Interventional Radiology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
 
Corresponding author: Prof WS Poon (wpoon@cuhk.edu.hk)
Abstract
Trousseau’s syndrome is defined as any unexplained thrombotic event that precedes the diagnosis of an occult visceral malignancy or appears concomitantly with a tumour. This report describes a young, previously healthy man diagnosed to have an acute middle cerebral arterial ischaemic stroke and lower-limb deep vein thrombosis, who subsequently succumbed to pulmonary arterial embolism. During the course of his illness, he was diagnosed to have a malignant pleural effusion secondary to an occult adenocarcinoma. This report highlights the need for a high degree of suspicion for occult malignancy and non-bacterial thrombotic endocarditis in young (<60 years old) ischaemic stroke patients with no identifiable conventional cardiovascular risks. In selected patients, transoesophageal echocardiography is the diagnostic investigation of choice, since transthoracic imaging is not sensitive. Screening tests for serum tumour markers and prompt heparinisation of these patients are suggested whenever ischaemic stroke secondary to malignancy-induced systemic hypercoagulability is suspected.
 
 
Case report
A 37-year-old Korean man, who was a non-smoker and previously healthy, experienced a sudden-onset right hemiparesis in April 2011. The patient was travelling in Guangzhou, China and was hospitalised within 4 hours of symptom onset. He was diagnosed to have a left middle cerebral artery (MCA) territory massive infarct based on plain computed tomography (CT). Contrast-enhanced magnetic resonance arteriography indicated a left proximal MCA occlusion (Fig a). The patient was treated conservatively and neither thrombolytic therapy nor operative management was given. Three days later, he was transferred to Hong Kong.
 

Figure. (a) Contrast-enhanced magnetic resonance angiograms on the day of symptom onset showing a left proximal middle cerebral artery (MCA) occlusion (white arrowhead). Brain computed tomography (CT) conducted 4 days later revealing haemorrhagic conversion of a left MCA region infarction with obliteration of (b) the basal cisterns and (c) midline shift. (d) Evidence of a left pleural effusion (black arrowhead) is present on the admission chest X-ray. (e) Deterioration in consciousness 8 days after symptom onset correlated with increased midline shift secondary to increased peri-haematomal oedema. (f) The 2-week postoperative CT showing satisfactory decompression and resolution of the intracerebral haematoma
 
On examination the patient had expressive aphasia and right hemiplegia. He was able to obey commands, had a Glasgow Coma Scale score of 11/15 (E4V1M6) and was afebrile. His blood pressure was not high and his pulse was regular, nor were carotid bruits or heart murmurs detected.
 
Repeat CT of the brain showed a massive left MCA territory infarction with haemorrhagic conversion and a chest X-ray revealed a left pleural effusion (Figs 1b-d). An electrocardiogram (ECG) showed no arrhythmias and initial blood test results showed a raised white cell count of 15.4 x 109 /L with neutrophilia. Other than that, the complete blood count, fasting serum glucose, lipid profile, and autoimmune markers were all within normal limits. The patient was initially managed medically with close neurological observations. In view of the neutrophilia, the patient was provisionally diagnosed to have bacterial endocarditis with complicating chest infection and parapneumonic pleural effusion. An echocardiogram was arranged and empirical intravenous antibiotics started.
 
Four days later, the patient became increasingly drowsy and an emergency decompressive craniectomy and duraplasty was performed (Figs 1e-f). The procedure was uneventful and the patient was stabilised.
 
As for delineating the cause for the stroke, all specimen culture results showed no evidence of an underlying infection. Percutaneous aspiration of the pleural effusion and pleural biopsy were performed. The biopsy showed no evidence of malignancy, but fluid cytology yielded adenocarcinoma cells. Serum tumour markers, including carcinoembryonic antigen and alpha-fetoprotein, were normal. The patient developed sinus tachycardia with an ECG showing a right heart strain pattern, before further cardiological tests (positron emission tomography and echocardiogram) could be performed. Blood for troponin-T and D-dimer levels were also elevated. The patient was subsequently diagnosed to have bilateral lower-limb deep vein thrombosis (DVT) extending from the external iliac vein to the popliteal vein. Thoracic CT was consistent with pulmonary embolism to the right lower lobe pulmonary arteries.
 
Subcutaneous low-molecular-weight heparin was started and an inferior vena cava (IVC) filter was placed. The patient's condition continued to deteriorate and he developed disseminated intravascular coagulopathy and respiratory failure. Progression of the pulmonary embolism was suspected, but the patient was deemed unsuitable for systemic thrombolysis due to his recent neurosurgery. The patient succumbed 2 weeks after the operation. A post-mortem examination was arranged, but waived by the coroner upon the family's request. The cause of death was pulmonary embolism contributed by an occult malignancy.
 
Discussion
Ischaemic stroke is the second most frequent neurological finding after brain metastases in post-mortem studies of cancer patients.1 From an autopsy study, cerebral infarction was observed in 15% of 3426 patients diagnosed with cancer, of whom half were previously symptomatic.1 In a recent single-centre retrospective review of 5106 patients admitted for ischaemic stroke, 24 (0.47%) were diagnosed to have an underlying malignancy. In this subgroup of patients, the mean age was relatively young (52 years) and there was a lower incidence of the typical vascular risk factor profiles as noted in larger stroke cohort studies.2
 
Trousseau first described the association between vascular thrombosis and cancer in his monograph of a peculiar migratory thrombophlebitis in 1865 and diagnosed the syndrome on himself 2 years later when he succumbed to gastric adenocarcinoma.3 4 There are several definitions for Trousseau's syndrome including "the occurrence of thrombophlebitis migrans with visceral cancer" and "spontaneous recurrent venous thromboses and/or arterial emboli caused by non-bacterial thrombotic endocarditis (NBTE) in a patient with malignancy".4 But a prima facie definition should be any "unexplained thrombotic event that precede[s] the diagnosis of an occult visceral malignancy or appear[s] concomitantly with the tumor".4
 
It is estimated that 15% of cancer patients will suffer from a thromboembolic event during the course of their illness and up to 50% have evidence of venous thromboembolism on post-mortem examination.5 The underlying pathophysiological mechanisms can be broadly classified as either due to the malignancy itself or as an iatrogenic complication of oncological treatment such as radiotherapy-induced arteriopathy. In turn, tumour-related ischaemic cerebrovascular events can be due to systemic hypercoagulability as part of a paraneoplastic syndrome, tumour emboli secondary to vessel infiltration, or contiguous compression of an artery. For this patient the thoracic CT revealed no evidence of infiltration of mediastinal great vessels or a cardiac lesion, so the possibility of arterial tumour emboli was unlikely. Brain magnetic resonance imaging also did not show brain metastasis. The fact that the patient developed extensive vascular thrombosis with bilateral lower-limb DVT and pulmonary embolism in spite of an IVC filter suggests that the cause of the stroke may have been due to malignancy-associated hypercoagulability.
 
The biological basis for systemic coagulopathy in Trousseau's syndrome has yet to be defined. It is thought to result from a complex interplay of tumour cell secretion of procoagulants and the host's blood vessels. When macrophages interact with malignant cells, there is a release of cytokines such as interleukin-1, interleukin-6, and tumour necrosis factor that can lead to endothelial damage and thrombogenesis on viable surfaces.6 Tumour cells may also secrete tissue factor and cysteine proteases with thromboplastin-like properties that activate coagulation factors VII and X. Finally mucin-producing adenocarcinomas can lead to direct non-enzymatic activation of factor X.7 In this state of hypercoagulability, the two commonest underlying mechanisms for ischaemic stroke are related to cardiogenic embolism from NBTE or cerebral intravascular coagulation.8
 
Non-bacterial thrombotic endocarditis
Up to half of patients with NBTE develop systemic emboli, most often to the cerebral vasculature and result in stroke, but some emboli also end up in the pulmonary, cardiac, and renal circulations.6 This may have been the underlying cause for the patient's massive MCA infarction and pulmonary embolism. Formally known as marantic endocarditis, the condition is characterised by sterile platelet and fibrin rich thrombi that form on previously undamaged heart valves.9 The incidence is largely unknown but according to Graus et al's autopsy series,1 it was noted in 1.6% of adult cancer patients. Often, it is encountered in patients with advanced-stage malignancies, in particular adenocarcinomas of the lung or gastro-intestinal tract; as in this patient, rarely NBTE can be a harbinger of occult cancer.8 10
 
Its pathogenesis is incompletely understood, but is possibly due to cytokine-mediated inflammatory valvular tissue injury that predisposes to thrombus formation.6 For several reasons, NBTE is difficult to diagnose. Thus, though aortic and mitral valves are the most commonly affected, patients seldom have detectable cardiac murmurs.6 11 Concomitantly, immunocompromised patients can suffer from infective endocarditis that confounds the diagnosis. Finally, transthoracic echocardiography is not sufficiently sensitive in detecting the smaller friable valvular vegetations of NBTE.12 Careful selection of patients for transoesophageal echocardiography, the preferred diagnostic test, is claimed to be preferable.6 Patients without end-stage malignancy, acceptable performance status of 3 or less on the Eastern Cooperative Oncology Group scale and with non-debilitating stroke are suitable candidates. For this patient, the diagnosis of NBTE was inferred in view of the negative culture and serology results and failed response to systemic antibiotics.
 
Treatment is directed at the underlying malignancy coupled with systemic anticoagulation. Since patients often present with metastatic disease, curative options are limited and anticoagulation should be administered indefinitely, since thromboembolic events tend to recur after discontinuation.6 Unfractionated heparin, given either intravenously or subcutaneously, has been proven to be most effective.6 Alternatively, low-molecular-weight heparin could be considered, but evidence about its utility is anecdotal. In contrast, vitamin K antagonists such as warfarin are not recommended, as recurrent thromboembolic events are common and expose the patient to unnecessary bleeding risks.6 13 The exact reason for warfarin resistance is unknown, but it has been suggested that thrombosis secondary to cytokine-induced inflammation is preferentially mediated by non-vitamin-K–dependent coagulation factors.13
 
Cerebral intravascular coagulation
Cerebral intravascular coagulation is a post-mortem pathological diagnosis made when cardiac valvulopathy is excluded. Originally described in autopsy studies among patients with leukaemia and breast cancer, this condition involves diffuse fibrinous occlusions of small cerebral blood vessels leading to micro-infarcts. Patients often present with progressive encephalopathy and seldom develop focal neurological deficits, although partial seizures have been reported.14 No reliable laboratory or radiological investigations are available to detect this disorder. Patients are usually in their preterminal state and management is often supportive.8
 
Conclusion
This patient suffered from a fatal manifestation of Trousseau's syndrome. One should be cognisant of the diagnosis of NBTE as a cause of ischaemic stroke in any patient with a known or suspected underlying malignancy. This is particularly true if new heart murmurs are detected in a cancer patient. Conversely, for a young patient (<60 years old), ischaemic stroke with no overt vascular risk factors should be considered for cancer screening. In selected cases, transoesophageal echocardiography appears to be the investigation of choice for NBTE. Anticoagulation, preferably with unfractionated heparin, should be administered as soon as possible in ischaemic stroke patients whenever such an event is a suspected consequence of an occult or overt malignancy causing systemic hypercoagulability.
 
References
1. Graus F, Rogers LR, Posner JB. Cerebrovascular complications in patients with cancer. Medicine (Baltimore) 1985;64:16-35. Crossref
2. Taccone FS, Jeangette SM, Blecic SA. First-ever stroke as initial presentation of systemic cancer. J Stroke Cerebrovasc Dis 2008;17:169-74. Crossref
3. Trousseau A. Lectures on clinical medicine, delivered at the Hotel-Dieu, Paris. 2nd ed. Philadelphia: Lindsay & Blakiston; 1865: 281-332.
4. Varki A. Trousseau's syndrome: multiple definitions and multiple mechanisms. Blood 2007;110:1723-9. Crossref
5. Deitcher SR. Cancer and thrombosis: mechanisms and treatment. J Thromb Thrombolysis 2003;16:21-31. Crossref
6. el-Shami K, Griffiths E, Streiff M. Nonbacterial thrombotic endocarditis in cancer patients: pathogenesis, diagnosis, and treatment. Oncologist 2007;12:518-23. Crossref
7. Bick RL. Cancer-associated thrombosis. N Engl J Med 2003;349:109-11. Crossref
8. Rogers LR. Cerebrovascular complications in cancer patients. Neurol Clin 2003;21:167-92. Crossref
9. Gross L, Friedberg CK. Nonbacterial thrombotic endocarditis. Classification and general description. Arch Intern Med (Chic) 1936;58:620-40. Crossref
10. Edoute Y, Haim N, Rinkevich D, Brenner B, Reisner SA. Cardiac valvular vegetations in cancer patients: a prospective echocardiographic study of 200 patients. Am J Med 1997;102:252-8. Crossref
11. Rosen P, Armstrong D. Nonbacterial thrombotic endocarditis in patients with malignant neoplastic diseases. Am J Med 1973;54:23-9. Crossref
12. Lee RJ, Bartzokis T, Yeoh TK, Grogin HR, Choi D, Schnittger I. Enhanced detection of intracardiac sources of cerebral emboli by transesophageal echocardiography. Stroke 1991;22:734-9. Crossref
13. Bell WR, Starksen NF, Tong S, Porterfield JK. Trousseau's syndrome. Devastating coagulopathy in the absence of heparin. Am J Med 1985;79:423-30. Crossref
14. Collins RC, Al-Mondhiry H, Chernik NL, Posner JB. Neurologic manifestations of intravascular coagulation in patients with cancer. A clinicopathologic analysis of 12 cases. Neurology 1975;25:795-806. Crossref

Scrotal wall metastasis as the first manifestation of primary gastric adenocarcinoma

Hong Kong Med J 2014;20:70–3 | Number 1, February 2014
DOI: 10.12809/hkmj133879
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Scrotal wall metastasis as the first manifestation of primary gastric adenocarcinoma
ST Leung, MB, BS, FRCR1; CY Chu, FRCR, FHKAM (Radiology)1; Billy MH Lai, MB, BS, FRCR1; Florence MF Cheung, FRCPath, FHKAM (Pathology)2; Jennifer LS Khoo, FRCR, FHKAM (Radiology)1
1 Department of Radiology, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong
2 Department of Clinical Pathology, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong
 
Corresponding author: Dr ST Leung (baryleung@hotmail.com)
Abstract
Metastases to the scrotal wall are very rare, and being the initial manifestation of occult primary tumours is even rarer. We report on a patient presenting with painless scrotal swelling, attributed to a solid extra-testicular mass found on ultrasonography. Subsequent investigations and surgical exploration revealed it to be a scrotal wall metastasis from an occult gastric primary. To our knowledge, this is the first report of a scrotal wall metastasis from gastric adenocarcinoma. The ensuing discussion and literature review highlight the diagnostic challenges posed by an extra-testicular scrotal metastasis from an occult primary tumour.
 
 
Introduction
Metastases from gastric adenocarcinoma to scrotal structures are rare, most being intra-testicular. Extra-testicular metastases are even rarer. It is extremely rare for such a metastasis to be the first manifestation of an occult primary tumour. Herein we report on a patient who presented with a solid extra-testicular mass, which was later confirmed to be a scrotal wall metastasis from an occult gastric adenocarcinoma. To our best knowledge, there has been no previous report of a scrotal wall metastasis from gastric adenocarcinoma.
 
Case report
A 66-year-old man, who enjoyed unremarkable past health, presented with a 2-week history of painless ‘right testicular’ swelling in May 2011. Examination yielded a 4-cm hard, irregular, and non-tender right scrotal mass.
 
An urgent ultrasound revealed an 18 x 13 x 21-mm solid extra-testicular mass with heterogeneous echogenicity in the right scrotum (Figs 1a-c), which was separate from the normal-looking right testis. Equivocal involvement of the right epididymis was noted on the ultrasound at that time. Increased vascularity of the mass lesion was noted on colour Doppler study. A small right hydrocele was also evident.
 

Figure 1. (a) Longitudinal and (b) transverse sonography of the right scrotum showing a solid extra-testicular mass separated from the normal-looking right testis. (c) Increased vascularity was evident on Doppler study. (d) Axial and (e) coronal computed tomographic images of the scrotum revealing bilateral scrotal soft-tissue thickening (arrows). (f) The oesophagogastroduodenoscopy reveals an irregular ulcerative tumour (*) over the lower part of gastric body
 
In view of a possible malignancy, the patient then underwent surgical scrotal exploration, which revealed a markedly thickened scrotal wall. The dartos muscles could not be well delineated and considered a probable sight of invasion by tumour, though the fat plane between the scrotal wall and the tunica was preserved. The testes could be well separated from the thickened scrotal wall.
 
A full-thickness scrotal wall incisional biopsy revealed diffuse infiltration of the subcutaneous tissue and dartos muscle by aggregates and islands of adenocarcinoma, more heavily on the right side. Evidence of a desmoplastic reaction was noted. The scrotal skin was unremarkable (Figs 2a-b).
 

Figure 2. Pathological examination showing that (a) the soft tissue underlying the scrotal skin was infiltrated by adenocarcinoma (H&E, x 20) and (b) malignant glands lined by pleomorphic cells seen in the dartos muscle (H&E, x 200). Immunohistochemical studies (x 200) showing (c) tumour cells positive for CK7, but (d) only focally positive for CK20, and (e) strongly positive for carcinoembryonic antigen and (f) partly positive for p53. The overall features favour a tumour from the upper gastro-intestinal or genital origin
 
Immunological studies showed that the tumour cells were positive for CK7, carcinoembryonic antigen, p53, and CDX2; focally positive for CK20 and negative for prostate-specific antigen (Figs 2c-f). These features favoured a tumour of the upper gastro-intestinal or genital origin. Biopsies of the urethra and urinary bladder from the same operation were negative of malignancy.
 
Subsequent computed tomography (CT) of the abdomen and pelvis to search for any underlying malignancy showed bilateral scrotal soft tissue thickening (Figs 1d-e), and oesophagogastroduodenoscopy revealed a hard, irregular, and circumferential ulcerative tumour over the lower part of body of stomach (Fig 1f). Biopsy of this ulcerative tumour revealed a poorly differentiated adenocarcinoma.
 
Palliative chemotherapy with the XELOX regimen (capecitabine plus oxaliplatin) was started. The chemotherapy regimen was subsequently changed to the FOLFOX regimen (folinic acid, fluorouracil, and oxaliplatin) because of progression of the gastric malignancy. He remained otherwise asymptomatic 10 months following the initial presentation, when this report was submitted for publication.
 
Discussion
The scrotum is a musculocutaneous sac composed of two compartments, divided by a midline septum. Each compartment contains a testis, epididymis, spermatic cord, and associated fascial coverings.1 The scrotal wall is composed of pigmented skin, subcutaneous tissue, and the closely related dartos fascia and dartos muscle.
 
Metastases to scrotal structures are rare. Among these, the testis is the most frequently involved site. Less than 3% of testicular malignancies are secondaries; the lung, prostate, and gastro-intestinal tract are the most common primary sites.2 3 Metastases to extra-testicular scrotal structures such as the epididymis, spermatic cord, and scrotal wall are even rarer. Metastases account for 8.1% of malignancies in the epididymis and spermatic cord,3 4 mostly reported as single case reports.3
 
Metastasis to the scrotal wall involving the subcutaneous tissue and dartos muscle with normal scrotal skin (as in our patient) is extremely rare. A previous review could only identify sporadic cases of scrotal wall metastases; the primaries being from malignant melanoma, anal carcinoma, and lung carcinoma.5 To our best knowledge, no scrotal wall metastasis from gastric adenocarcinoma has ever been reported in the literature. On the other hand, cutaneous metastases involving the scrotal skin alone are relatively more common. In contrast to scrotal wall metastases which present as a scrotal swelling, scrotal skin metastases present as cutaneous polypoid lesions, ulcers, or papules.6 7 8
 
Several pathways by which primary tumours metastasise to the scrotal structures have been proposed. They include retrograde venous embolism, retrograde lymphatic extension, arterial embolism, direct invasion along the testicular cord, and transperitoneal seeding through a congenital hydrocele.9 Although the exact pathway of the metastasis in our patient is not clear, absence of intra-abdominal, pelvic lymphadenopathy, and testicular cord thickening all favour embolism or transperitoneal seeding as the route.
 
Clinically, a scrotal wall metastasis usually presents as a painless scrotal swelling with normal overlying skin, with a firm-to-hard mass being evident on physical examination. Ultrasonography usually reveals a solid extra-testicular mass, that is mostly hypoechoic but can have variable echogenicity.2 Previously described sonographic features of a scrotal wall metastasis from a lung primary also entailed increased peripheral vascularity and poor delineation with the epididymis,2 in which the features were also observed in our patient.
 
Ultrasonography is usually the first imaging modality for evaluating patients presenting with scrotal swelling. Its high spatial resolution provides nearly 100% sensitivity in identifying a scrotal mass and a 98 to 100% sensitivity in differentiating intra-testicular versus extra-testicular lesions.1 The two most important factors to consider during evaluation of a scrotal mass are whether it is intra- or extra-testicular in location, and whether it is cystic or solid in nature.1 This is because more than 95% intra-testicular masses are malignant while most that are extra-testicular are benign.10
 
Most extra-testicular masses are cystic and almost all are benign.1 Solid extra-testicular masses are uncommon and 97% of them are also benign.1 11 Among these solid extra-testicular masses, lipoma and adenomatoid tumours are most frequently encountered, and account for about 45% and 33% of all extra-testicular masses, respectively.11
 
Malignancies account for the remaining 3% of extra-testicular masses. It was estimated that 8.1% of malignancies in the epididymis and spermatic cord are due to metastases.3 4 Rhabdomyosarcoma is the most common primary malignant tumour, accounting for 40% of all malignant extra-testicular tumours and are most common in infants and children.11 In adults, examples of primary malignant tumours include leiomyosarcoma, liposarcoma, fibrosarcoma, malignant fibrous histiocytoma, and primary adenocarcinoma of epididymis.5
 
Secondary extra-testicular malignant tumours usually occur against a background of known advanced malignancy. Common primary sites include prostate, kidney, gastro-intestinal tract, and pancreas.11 Epididymis and spermatic cord are the usual sites of involvement, while scrotal wall metastases are extremely rare. Only sporadic case reports can be identified in the literature for metastases to the scrotal wall (from melanoma, anal carcinoma, and lung carcinoma).2 12
 
Lesion diameter, volume, and presence of vascularity on Doppler ultrasonography assist differentiation of malignant from benign lesions.13 Multifocal lesions and heterogeneity have also been suggested as supporting metastatic disease.14 15 However, in most instances, considerable overlap in sonographic appearances of many solid extra-testicular masses preclude a specific diagnosis.1
 
Magnetic resonance imaging (MRI) is useful in characterising certain extra-testicular lesions such as lipoma, haematoma, and fibrous pseudotumour. Enhancement patterns in gadolinium-enhanced MRIs are also useful in differentiating malignant from benign lesions. In such cases, MRI findings may obviate the need for surgery or change the surgical approach.14
 
In patients without a known history of malignancy such as ours, diagnosis of an extra-testicular metastasis on the initial ultrasound is difficult. The sonographic differential diagnosis includes other extra-testicular benign and malignant tumours. Clinical correlation is essential to enable better differentiation of malignant from benign lesions. The clinical finding of a hard scrotal mass in our patient raised concerns of malignancy, and hence surgical exploration was undertaken. The final diagnosis still depends on biopsy and pathological study. In our patient, histology and immunological studies of the scrotal wall biopsy hinted at the final diagnosis of occult gastric adenocarcinoma. Although positron emission tomography–CT may be useful for seeking an occult primary malignancy, it is not commonly used as a first-line imaging modality in patients presenting with a scrotal wall lesion. However, it could be offered to search for an underlying primary when histology shows adenocarcinoma but immunological study results are pending.
 
Conclusion
Extra-testicular metastases are rare and have non-specific sonographic features, which always pose difficulties in diagnosis, particularly in patients without a known primary malignancy. We hereby report the first case of a gastric adenocarcinoma presenting as scrotal wall metastasis. This case also demonstrates the importance of radiological, clinical, and pathological correlations in making the final diagnosis.
 
References
1. Woodward PJ, Schwab CM, Sesterhenn IA. From the archives of the AFIP: extratesticular scrotal masses: radiologic-pathologic correlation. Radiographics 2003;23:215-40. Crossref
2. Dogra V, Saad W, Rubens DJ. Sonographic appearance of scrotal wall metastases from lung adenocarcinoma. AJR Am J Roentgenol 2002;179:1647-8. Crossref
3. Dutt N, Bates AW, Baithun SI. Secondary neoplasms of the male genital tract with different patterns of involvement in adults and children. Histopathology 2000;37:323-31. Crossref
4. Algaba F, Santaularia JM, Villavicencio H. Metastatic tumor of the epididymis and spermatic cord. Eur Urol 1983;9:56-9.
5. Dogra VS, Gottlieb GH, Oka M, Rubens DJ. Sonography of the scrotum. Radiology 2003;227:18-36. Crossref
6. Aridogan IA, Satar N, Doran E, Tansug MZ. Scrotal skin metastases of renal cell carcinoma: a case report. Acta Chir Belg 2004;104:599-600.
7. McWeeney DM, Martin ST, Ryan RS, Tobbia IN, Donnellan PP, Barry KM. Scrotal metastases from colorectal carcinoma: a case report. Cases J 2009;2:111. Crossref
8. Wang SQ, Mecca PS, Myskowski PL, Slovin SF. Scrotal and penile papules and plaques as the initial manifestation of a cutaneous metastasis of adenocarcinoma of the prostate: case report and review of the literature. J Cutan Pathol 2008;35:681-4. Crossref
9. Hanash KA, Carney JA, Kelalis PP. Metastatic tumors to the testicles: routes of metastasis. J Urol 1969;102:465-8.
10. Moghe PK, Brady AP. Ultrasound of testicular epidermoid cysts. Br J Radiol 1999;72:942-5.
11. Akbar SA, Sayyed TA, Jafri SZ, Hasteh F, Neill JS. Multimodality imaging of paratesticular neoplasms and their rare mimics. Radiographics 2003;23:1461-76. Crossref
12. Ferguson MA, White BA, Johnson DE, Carrington PR, Schaefer RF. Carcinoma en cuirasse of the scrotum: an unusual presentation of lung carcinoma metastatic to the scrotum. J Urol 1998;160(6 Pt 1):2154-5.
13. Alleman WG, Gorman B, King BF, Larson DR, Cheville JC, Nehra A. Benign and malignant epididymal masses evaluated with scrotal sonography: clinical and pathologic review of 85 patients. J Ultrasound Med 2008;27:1195-202.
14. Cassidy FH, Ishioka KM, McMahon CJ, et al. MR imaging of scrotal tumors and pseudotumors. Radiographics 2010;30:665-83. Crossref
15. Souza FF, Di Salvo D. Sonographic features of a metastatic extratesticular gastrointestinal stromal tumor. J Ultrasound Med 2008;27:1639-42.

Transnasal penetrating intracranial injury with a chopstick

Hong Kong Med J 2014;20:67–9 | Number 1, February 2014
DOI: 10.12809/hkmj134028
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Transnasal penetrating intracranial injury with a chopstick
SK Chan, MB, BS; KY Pang, FRCS, FHKAM (Surgery); CK Wong, FRCS, FHKAM (Surgery)
Department of Neurosurgery, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong
 
Corresponding author: Dr SK Chan (skc2009@hotmail.com)
Abstract
We report the first case of a transnasal penetrating intracranial injury in Hong Kong by a chopstick. A 49-year-old man attempted suicide by inserting a wooden chopstick into his left nose and then pulled it out. The chopstick caused a transnasal penetrating brain injury, confirmed by contrast magnetic resonance imaging of the brain. He was managed conservatively. Later he developed meningitis without a brain abscess and was prescribed antibiotics for 6 weeks. He enjoyed a good neurological recovery. This case illustrates that clinician should have a high index of suspicion for penetrating intracranial injury due to a nasally inserted foreign body, even though it had already been removed. In such cases moreover, brain magnetic resonance imaging is the imaging modality of choice, as it can delineate the path of penetration far better than plain computed tomography.
 
 
Case report
A 49-year-old Chinese man, who was a psychiatric in-patient, self-inserted a wooden chopstick into his left nose and then pulled it out in November 2012. He was subsequently assessed by an ear, nose and throat surgeon. No nasal foreign body was seen and there was no epistaxis. Brain computed tomography (CT) 6 hours after the injury showed a trace amount of haemorrhage over the right gyrus rectus and a small amount of pneumocephalus over the right anterior fossa (Fig 1), and hence the neurosurgical unit was consulted. Six hours after the incident his vital signs were stable and he was afebrile; his Glasgow Coma Scale score was E4M6V4. His speech appeared confused, as if in a premorbid state. There was no neurological deficit, and no cerebrospinal fluid (CSF) rhinorrhoea upon stress testing. Contrast magnetic resonance imaging (MRI) of the brain was performed on the next day, which showed a long haemorrhagic tract extending from right paramidline anterior skull base, coursing postero-superiorly across medial right frontal lobe, closely adjacent to the right frontal horn, and ending at the vertex region (Fig 2), and a trace of intraventricular haemorrhage. On the same day he developed fever. Lumbar puncture yielded turbid CSF, with the presence of Gram-positive cocci, as well as low CSF glucose and high CSF protein concentrations. Conservative management was adopted. On an empirical basis, intravenous ceftriaxone, vancomycin, and metronidazole were prescribed. Prophylactic anticonvulsant therapy (phenytoin) was also given. The CSF culture grew Staphylococcus aureus and Citrobacter koseri. The antibiotic regimen was switched to intravenous ceftriaxone and oral metronidazole. The patient’s recovery was excellent, as reflected by normalisation of body temperature and inflammatory markers. On day 14, contrast CT brain showed no abscess. He was well after 6 weeks of antibiotic treatment.
 

Figure 1. Plain computed tomographic scan of brain (axial cut) showing pneumocephalus (black arrow) and haemorrhage over right gyrus rectus (white arrowhead)
 

Figure 2. (a) T2-weighted magnetic resonance imaging (MRI) scan of brain (sagittal cut) showing transected track (black arrows). (b) T2-weighted MRI scan of brain in fluid-attenuated inversion recovery sequence (axial cut) showing transected track (white arrows)
 
Discussion
A literature search of the MEDLINE database (using the key words "transnasal" and "penetrating intracranial injury", or the other similar keywords) was conducted. Approximately 10 case reports were identified, indicating this was an exceedingly rare condition. We report the first case of a transnasal penetrating intracranial injury in Hong Kong by means of a chopstick. The majority of patients with this mechanism of injury were due to accidental falls on objects that enter the nostril,1 while few were due to attempted suicide. This mode of penetrating intracranial injury can result in severe complications, including CSF rhinorrhoea and infection (meningitis and/or brain abscess).2 The source of the bacteria could have been from the chopstick or the normal flora in the nasal cavity/paranasal sinuses. Such injury can also result in blindness or ophthalmoplegia,3 if the orbital cavity is involved. The most dreadful complication is severe haemorrhage due to internal carotid artery injury, which may lead to immediate death.1 Although foreign body in the nose is a common presentation, clinicians should always have a high index of suspicion for possible transnasal penetrating intracranial injury. Such vigilance is especially necessary in patients who cannot volunteer a clear history or complaint (eg children or psychiatric patients), are febrile, have a neurological deficit, or have continuous epistaxis.
 
All patients with penetrating brain injury should have adequate neuroradiological examinations.4 Plain CT brain is the initial investigation of choice to explore for the presence of any retained radio-opaque material. It can also reveal presence of an intracranial haematoma or air, or focal heterogeneous hypodensity suggestive of brain abscess. Contrast MRI of the brain with cerebral angiography is the best method of evaluating penetrating brain injuries. Besides the previously mentioned abnormal findings, it can also delineate the track transected by the foreign body, even after it has been removed, as in this case. Had contrast MRI brain not been arranged for this patient, penetrating brain injury would probably have been missed, given the seemingly unalarming brain CT (Fig 1). Brain abscess or vascular damage, if any, can also be appreciated using brain MRI.
 
Management depends on patient’s condition and whether a complication has developed. Neuroendoscopy is a useful operative tool, which can be employed to remove foreign body or repair the dural defect causing CSF rhinorrhoea,5 whenever conservative management fails. Craniotomy may be warranted if there is a sizable abscess or cerebral haemorrhage. Since the patient did not have these complications, he was managed conservatively. Initially, he received empirical intravenous broad-spectrum antibiotics, as for the treatment of a bacterial cerebral abscess. The CSF should be obtained and cultured if the patient has a fever. Targeted antibiotics can then be used depending on the sensitivity results. The patient was also instructed to lie flat to prevent CSF leakage. Short-term prophylactic anticonvulsant should also be prescribed.
 
Conclusion
Herein we report the first patient with a transnasal penetrating intracranial injury in Hong Kong resulting from a chopstick. Such injuries confer significant mortality or morbidity, for which clinicians should always have a high index of suspicion. The neuroimaging of choice involves contrast MRI brain with cerebral angiography. Operative management can be considered for those patients who have a foreign body in situ, a sizable abscess or haemorrhage, or CSF rhinorrhoea.
 
References
1. Ihama Y, Nagai T, Ninomiya K, Fukasawa M, Fuke C, Miyazaki T. A transnasal intracranial stab wound by a plastic-covered umbrella tip. Forensic Sci Int 2012;214:e9-e11. Crossref
2. Hiraishi T, Tomikawa M, Kobayashi T, Kawaquchi T. Delayed brain abscess after penetrating transorbital injury [in Japanese]. No Shinkei Geka 2007;35:481-6.
3. Liu SY, Cheng WY, Lee HT, Shen CC. Endonasal transsphenoidal endoscopy-assisted removal of a shotgun pellet in the sphenoid sinus: a case report. Surg Neurol 2008;70 Suppl 1:S1:56-9.
4. Sharif S, Roberts G, Phillips J. Transnasal penetrating brain injury with a ball-pen. Br J Neurosurg 2000;14:159-60.  Crossref
5. Lee DH, Seo BR, Lim SC. Endoscopic treatment of transnasal intracranial penetrating foreign body. J Craniofac Surg 2011;22:1800-1. Crossref

Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome: a treatable genetic liver disease warranting urgent diagnosis

Hong Kong Med J 2014;20:63–6 | Number 1, February 2014
DOI: 10.12809/hkmj133826
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome: a treatable genetic liver disease warranting urgent diagnosis
Hencher HC Lee, MA, FRCPA1; KH Poon, FHKAM (Paediatrics)2; CK Lai, MSc1; KM Au, MSc1; TS Siu, MPhil3; Judy PS Lai, MSc4; Chloe M Mak, PhD, FHKAM (Pathology)1; YP Yuen, MSc, FHKAM (Pathology)1; CW Lam, PhD, FHKAM (Pathology)5; Albert YW Chan, MD, FHKAM (Pathology)1
1 Department of Pathology, Princess Margaret Hospital, Laichikok, Hong Kong
2 Department of Paediatrics and Adolescent Medicine, Tuen Mun Hospital, Tuen Mun, Hong Kong
3 Division of Clinical Biochemistry, Queen Mary Hospital, Pokfulam, Hong Kong
4 Department of Clinical Pathology, Tuen Mun Hospital, Tuen Mun, Hong Kong
5 Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
 
Corresponding author: Dr CW Lam (ching-wanlam@pathology.hku.hk)
Abstract
Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is an autosomal recessive disorder caused by a defect in ornithine translocase. This condition leads to variable clinical presentations, including episodic hyperammonaemia, hepatic derangement, and chronic neurological manifestations. Fewer than 100 affected patients have been reported worldwide. Here we report the first two cases in Hong Kong Chinese, who were compound heterozygous siblings for c.535C>T (p.Arg179*) and c.815C>T (p.Thr272Ile) in the SLC25A15 gene. When the mother refused prenatal diagnosis for the second pregnancy, urgent genetic testing provided the definitive diagnosis within 24 hours to enable specific treatment. Optimal management of these two patients relied on the concerted efforts of a multidisciplinary team and illustrates the importance of an expanded newborn screening service for early detection and treatment of inherited metabolic diseases.
 
 
Introduction
The urea cycle is the major pathway of nitrogen metabolism in the human body. Excess nitrogen, in the form of ammonia, is converted via this cycle to urea and excreted through the kidneys. In humans, the cycle entails five key enzymes, including carbamoyl-phosphate synthetase I (CPS1), ornithine transcarbamylase (OTC), argininosuccinate synthetase, argininosuccinate lyase, and arginase; while an additional enzyme named N-acetylglutamate synthase provides CPS1 with its essential cofactor.1 A defect in any of these six enzymatic pathways or the two associated transporters, namely citrin and ornithine translocase, causes urea cycle disorders.2 Patients with complete deficiency of the affected enzyme present with significant hyperammonaemia in the neonatal period. It is a serious and often lethal condition or causes irreversible brain damage especially when the diagnosis or treatment is delayed or ineffective. On the other hand, patients with partial enzyme deficiencies or defective transporters can present later in life, from infancy to adulthood, and manifest whenever the urea cycle is overwhelmed by environmental triggers or stresses. These result in acute hyperammonaemic episodes.2
 
Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome (HHH syndrome; MIM#238970) is an autosomal recessive disorder caused by a defect in ornithine translocase (SLC25A15 or ORNT1, MIM*603861). The disorder is exceedingly rare; with fewer than 100 patients having been reported worldwide, although its incidence in northern Saskatchewan in Canada was estimated to be 1 in 1500 (with a carrier rate of 1 in 19).3 The syndrome was first described by Shih et al4 in 1969 with a neurological phenotype entailing seizures and mental retardation. It was later found that the clinical presentations of HHH syndrome can be highly variable, and include spastic paraplegia, pyramidal and extrapyramidal signs, stroke-like episodes, hypotonia, seizures, ataxia, protein intolerance, failure to thrive, and hepatic failure.5 6 7 Liver biopsies typically reveal vacuolated hepatocytes distended with glycogen on light microscopy and bizarre-looking mitochondria on electronic microscopy.8 So far, no definite genotype-phenotype correlation has been noted, with a high degree of clinical heterogeneity even among patients harbouring the same genetic defect.9 However, patients with HHH syndrome can respond well to a low-protein diet with improvements in neurological symptoms and hepatic function, for which reason an accurate diagnosis is critical to management.5 10 For the first time in Hong Kong, here we describe HHH syndrome in a pair of siblings and their clinical, biochemical, and molecular profiles, with a view to facilitate understanding of this disorder in our locality. The diagnosis of this family also revealed a possible founder mutation in ethnic Chinese.
 
Case report
The patient was an ethnic Han Chinese boy, born healthy to a non-consanguineous couple and fed on both human and formula milk in 2007. He presented with neonatal jaundice with serum bilirubin up to 338 µmol/L (diazo method) or 295 µmol/L (photometric method) on day 5, which dropped to 179 µmol/L (photometric method) on day 6 after phototherapy. He was then discharged without further blood taking, since otherwise he was clinically well. However, 1 month later he presented with persistent jaundice and a liver palpable 2 cm below the costal margin but no clinical splenomegaly. The total bilirubin was 99 µmol/L with a direct bilirubin of 27 (reference range [RR], 1-5) µmol/L and an alkaline phosphatase (ALP) of 529 (RR, 82-383) U/L. His γ-glutamyltransferase (GGT) ranged from 345 to 388 (reference level, <220) U/L but the alanine transaminase (ALT) was normal at 32 to 35 (RR, 4-35) U/L. While his bilirubin and GGT levels gradually normalised at 2 months, even at 12 months the ALT remained elevated at 311 U/L and the ALP was 418 U/L (RR, 104-345 U/L). A deranged clotting profile with a prothrombin time of 20.5 (RR, 10.4-12.6; international normalised ratio, 2.0) seconds, an activated partial thromboplastin time of 36.3 (RR, 26.4-35.3) seconds, and a serum bile acid level of 10.8 (reference level, <7) μmol/L were noted. At this juncture, his liver remained palpable, 1 cm below the costal margin. In addition, he was noted to have alpha thalassaemia trait.
 
At the age of 11 months, gas chromatography–mass spectrometry of urine detected significant hyperexcretion of uracil and moderately excessive excretion of orotic acid, while he was taking an unrestricted protein diet (approximately 3 g/kg/day). He also had homocitrullinuria of up to 71 (reference level, <9) μmol/mmol creatinine, which was also demonstrated by liquid chromatography–tandem mass spectrometry. Plasma amino acids analysis by high-performance liquid chromatography detected excessive alanine, arginine, ornithine, and methionine concentrations, postprandially (Fig). At the age of 12 months, the blood ammonia was elevated at 132 (RR, 16-60) µmol/L, the simultaneous blood glucose was 3.8 mmol/L, and the lactate was 2.5 (RR, 0.5-2.2) mmol/L. The biochemical picture was suggestive of urea cycle dysfunction. Interestingly, at that juncture he was clinically well and had no vomiting or encephalopathy. His blood ammonia decreased to 59 µmol/L on rechecking after 24 hours just before institution of protein restriction (0.9 g/kg/day); over the next 14 days it fluctuated between 43 and 84 µmol/.
 

Figure. The amino acid profile of the proband on different occasions
 
Mutational analysis was performed by polymerase chain reaction and Sanger sequencing with genomic DNA. While no mutation was noted in the OTC gene, the patient was shown to be heterozygous for two different mutations, c.535C>T (p.Arg179*) and c.815C>T (p.Thr272Ile), in the SLC25A15 gene. The latter missense mutation was not found in 100 Chinese control chromosomes tested. Compound heterozygosity was confirmed by analysing the parental DNA.
 
The patient's liver became impalpable 1 month after therapy. Normalisation of the serum ALT level was noted 1 month after treatment, although plasma ornithine and urine orotic acid levels remained elevated. Coagulation factor VII and X levels were normal during convalescence. At the age of 6 years, the boy had no acute encephalopathy or pyramidal signs, but did exhibit mild clumsiness and subtle gait ataxia (only evident on tandem walking).
 
The mother became pregnant 1 year later in 2009, when the proband was 2 years old. In view of the family history of HHH syndrome, counselling was provided by the obstetrician early during gestation, yet the parents opted not to obtain a prenatal diagnosis. Prior arrangement was then made with the chemical pathologist to have a semi-urgent molecular diagnosis to facilitate therapy for the neonate if necessary. This younger brother was immediately started on a low protein (≤1.2 g/kg/day) diet, which consisted of breastfeeding and a zero-protein formula after delivery. Aged 12 hours, the postprandial blood ammonia was 68 µmol/L (reference level, <100 µmol/L) and blood for molecular genetics was sampled simultaneously. The boy only had physiological jaundice and no other signs, but was also soon confirmed to have a compound heterozygous form of the two familial mutations about which the paediatrician was notified within 24 hours of blood sampling. In view of the prompt definitive diagnosis, protein restriction was continued with confidence. His ammonia peaked at 111 µmol/L and then normalised, whilst his ALT level remained normal in the neonatal period. His coagulation factors VII and X levels were also normal. The boy did not have any episodes of acute encephalopathy and developed normally when seen for follow-up at the age of 3 years.
 
Discussion
When arginase cleaves arginine in the last step of the urea cycle to produce urea and ornithine, the ornithine translocase enzyme transports cytosolic ornithine back into the mitochondria for subsequent urea cycles in exchange of mitochondrial citrulline.11 The gene SLC25A15 was cloned in 1999 and found to account for the HHH syndrome,12 and molecular modelling was reported early in 2012.13 A founder mutation p.Phe188del was reported in French-Canadian patients,12 and in Japanese patients the p.Arg179* mutation was also noted to be frequent.14 15
 
The nonsense mutation p.Arg179* variant is predicted to cause premature termination of the protein. Although common in Japan,14 it was also reported in other ethnic groups.15 The missense mutation p.Thr272Ile was reported in 2009 by Tessa et al15 in one Taiwanese patient, with recently published functional proof of its pathogenicity. However, this missense mutation has never been reported in other ethnic groups. We therefore postulate that it could be a common mutation, possibly having an ancestral founder gene effect in ethnic Chinese. If this is confirmed in more patients of Chinese ethnicity, it may aid prioritising workflow for the genetic testing of individuals suspected to have HHH syndrome. In which case, they could undergo more focused molecular investigation instead of whole gene sequencing. Consequently, a more rapid diagnosis could enable more prompt and appropriate treatment.
 
To the best of our knowledge, these were the first two cases of HHH syndrome reported in Hong Kong. The proband’s metabolic profile in early infancy was particularly illustrative of the natural course of the associated hepatic disease. The untreated first child had pronounced neonatal jaundice which responded to phototherapy and soon evolved into mild transient hyperbilirubinaemia with an accompanying elevation in serum ALP but not ALT levels in early infancy. Subsequently, despite resolution of jaundice, he showed moderate hepatocellular derangement and dysfunction with a coagulopathy and hyperammonaemia, which responded to protein restriction. The younger brother had no serum ALT level elevation while the ammonia level was only mildly raised in the first week of life, at which time he was proactively commenced on protein restriction. These two cases demonstrate that metabolic profiling, including the ammonia level, should be included in the initial workup for any infant with unexplained prolonged liver dysfunction and may provide a clue to a possible underlying defect in the urea cycle. The HHH syndrome is rare, yet a readily treatable cause to consider in Chinese patients with unusual plasma amino acid patterns. In addition, modern medical technologies (eg tandem mass spectrometry) allow multiplex screening of classical inherited metabolic disorders that can detect HHH syndrome using hyperornithinaemia as the disease marker.16 The successful diagnosis and management of these siblings entailed a concerted effort and collaboration of a multidisciplinary team. Notably, the diagnosis of rare diseases is often difficult, and the importance of having an integrated pathology service is crucial.
 
Prenatal diagnosis for the younger brother was possible but declined by the parents, making timely intervention of the chemical pathology laboratory even more critical for establishing or excluding the diagnosis in the neonate. In this clinical setting, a rapid and definitive diagnosis (within 24 hours) provided by genetic testing was important as a mildly elevated ammonia level in an asymptomatic newborn may be hard to interpret. It allowed the clinicians to counsel the parents accordingly on the need for lifelong protein restriction to minimise the chance of decompensation. Although late-onset long-term neurological sequelae may not be preventable,9 it is prudent to keep the two children metabolically stable as far as possible, to mitigate brain damage from decompensation.
 
In conclusion, HHH syndrome, although very rare, is an inborn error of metabolism that can occur in the Chinese and is readily detectable by tandem mass spectrometry.17 If this technique could be introduced to support a local newborn screening programme, many more possibly treatable metabolic disorders may be picked up.
 
References
1. Häberle J. Clinical practice: the management of hyperammonemia. Eur J Pediatr 2011;170:21-34. Crossref
2. Mitchell S, Ellingson C, Coyne T, et al. Genetic variation in the urea cycle: a model resource for investigating key candidate genes for common diseases. Hum Mutat 2009;30:56-60. Crossref
3. Sokoro AA, Lepage J, Antonishyn N, et al. Diagnosis and high incidence of hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome in northern Saskatchewan. J Inherit Metab Dis 2010;33 Suppl 3:275-81. Crossref
4. Shih VE, Efron ML, Moser HW. Hyperornithinemia, hyperammonemia, and homocitrullinuria. A new disorder of amino acid metabolism associated with myoclonic seizures and mental retardation. Am J Dis Child 1969;117:83-92. Crossref
5. Al-Hassnan ZN, Rashed MS, Al-Dirbashi OY, Patay Z, Rahbeeni Z, Abu-Amero KK. Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome with stroke-like imaging presentation: clinical, biochemical and molecular analysis. J Neurol Sci 2008;264:187-94. Crossref
6. Lemay JF, Lambert MA, Mitchell GA, et al. Hyperammonemia-hyperornithinemia-homocitrullinuria syndrome: neurologic, ophthalmologic, and neuropsychologic examination of six patients. J Pediatr 1992;121:725-30. Crossref
7. Gatfield PD, Taller E, Wolfe DM, Haust MD. Hyperornithinemia, hyperammonemia, and homocitrullinuria associated with decreased carbamyl phosphate synthetase I activity. Pediatr Res 1975;9:488-97. Crossref
8. Haust MD, Gordon BA. Ultrastructural changes in the mitochondria in disorders in ornithine metabolism. Pediatr Res 1980;14:1411. Crossref
9. Debray FG, Lambert M, Lemieux B, et al. Phenotypic variability among patients with hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome homozygous for the delF188 mutation in SLC25A15. J Med Genet 2008;45:759-64. Crossref
10. Gjessing LR, Lunde HA, Undrum T, Broch H, Alme A, Lie SO. A new patient with hyperornithinaemia, hyperammonaemia and homocitrullinuria treated early with low protein diet. J Inherit Metab Dis 1986;9:186-92. Crossref
11. Palmieri F. The mitochondrial transporter family (SLC25): physiological and pathological implications. Pflugers Arch 2004;447:689-709. Crossref
12. Camacho JA, Obie C, Biery B, et al. Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter. Nat Genet 1999;22:151-8. Crossref
13. Wang JF, Chou KC. Insights into the mutation-induced HHH syndrome from modeling human mitochondrial ornithine transporter-1. PLoS One 2012;7:e31048. Crossref
14. Miyamoto T, Kanazawa N, Kato S, et al. Diagnosis of Japanese patients with HHH syndrome by molecular genetic analysis: a common mutation, R179X. J Hum Genet 2001;46:260-2. Crossref
15. Tessa A, Fiermonte G, Dionisi-Vici C, et al. Identification of novel mutations in the SLC25A15 gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome: a clinical, molecular, and functional study. Hum Mutat 2009;30:741-8. Crossref
16. Chace DH, Kalas TA, Naylor EW. Use of tandem mass spectrometry for multianalyte screening of dried blood specimens from newborns. Clin Chem 2003;49:1797-817. Crossref
17. Lee HC, Mak CM, Lam CW, et al. Analysis of inborn errors of metabolism: disease spectrum for expanded newborn screening in Hong Kong. Chin Med J (Engl) 2011;124:983-9.

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