A family with a strong history of pneumothorax was referred to our genetic clinic for assessment. There were three siblings who had all developed spontaneous pneumothorax at the age of 30, 58, and 59 years. All were non-smokers with no pre-existing pulmonary disease. High-resolution computed tomography of the thorax for all showed multiple thin-walled pulmonary cysts of variable size on both sides, mainly located at the basal and peripheral lung regions (Fig). Lung biopsy was not informative. Physical examination revealed multiple smooth, dome-shaped papules over the face and ears in one of siblings (Fig b). There were no other features of tuberous sclerosis or history of renal disease in the family. Based on the dermatological findings and diffuse multicystic lung disease, Birt-Hogg-Dubé (BHD) syndrome was suspected. FLCN gene analysis revealed a heterozygous FLCN{NM_144997.5}:c.1285dupC mutation in all affected members. The diagnosis of BHD syndrome was substantiated. Renal imaging was arranged for surveillance of potential renal cell carcinoma.

The BHD syndrome is a rare autosomal dominant disease characterised by three major organ manifestations1:

(1) Fibrofolliculomas and other benign skin tumours such as trichodiscomas and acrochordons; these skin lesions are predominantly located on the facial, cervical, and upper truncal regions as smooth, dome-shaped, and white to flesh-coloured papules.

(2) Increased susceptibility to renal cell carcinoma of mixed histologies; the most frequent subtype is a hybrid oncocytic tumour with features of renal oncocytoma and chromophobe renal cell carcinoma.

(3) Multiple bilateral pulmonary cysts and spontaneous pneumothorax.

The clinical features of BHD syndrome are heterogeneous with wide intra-familial and inter-familial variation. It is caused by mutations of the FLCN gene. Any combination of the cutaneous, renal, and pulmonary features mentioned above present in an individual or multiple family members should alert the clinician to the possibility of BHD syndrome.

Bilateral multiple pulmonary cysts are a highly penetrant feature in BHD syndrome. As a result, the risk of pneumothorax in BHD patients is 50 times higher than that of the general population.2 Approximately 80% to 90% of BHD patients develop lung cysts, usually after early mid-adulthood. The BHD-associated lung cysts tend to be located at the basilar and mediastinal regions of the lungs, in contrast to the typically apical location in primary spontaneous pneumothorax and emphysema. Radiologically, the BHD-associated lung cysts are usually irregularly shaped, variable in size and number, and with sharply demarcated thin walls that do not enhance on computed tomographic imaging.

Fibrofolliculomas are present in more than 80% of patients with BHD syndrome and typically appear after the age of 20 years. They are dome-shaped, white to flesh-coloured, non-painful and non-pruritic papules located on the facial, cervical, and upper truncal regions.

The most threatening complication of BHD syndrome is renal cell carcinoma. It occurs in approximately 15% of BHD patients by the age of 70 years.3 Therefore regular surveillance is mandatory.

Physicians should be alert to the possibility of BHD syndrome in a patient who presents with diffuse cystic lung disease, particularly in the presence of a positive family history. Early referral to a clinical genetic service and multidisciplinary management is recommended. Early diagnosis and regular renal surveillance aim to greatly reduce renal cell carcinoma–associated morbidity and mortality.

1. Menko FH, van Steensel MA, Giraud S, et al. Birt-Hogg-Dubé syndrome: diagnosis and management. Lancet Oncol 2009;10:1199-206. Crossref

2. Gupta N, Seyama K, McCormack FX. Pulmonary manifestations of Birt-Hogg-Dubé syndrome. Fam Cancer 2013;12:387-96. Crossref

3. Stamatakis L, Metwalli AR, Middelton LA, Marston Linehan W. Diagnosis and management of BHD-associated kidney cancer. Fam Cancer 2013;12:397-402. Crossref

An 88-year-old male with no underlying disease presented to our emergency department in March 2015 with a 2-week history of right flank pain but no fever or urinary tract symptoms. He was conscious, alert, and well-oriented. His blood pressure was 145/89 mm Hg, with a heart rate of 82 beats/min and respiratory rate of 16 breaths/min on arrival. Physical examination revealed obvious right flank knocking tenderness. Laboratory testing revealed white blood cell (WBC) count of 34.7 x 10⁹ /L (reference range [RR], 4.5-11.0 x 10⁹ /L), haemoglobin level of 95 g/L (RR, 135-175 g/L), platelet count of 496 x 10⁹ /L (RR, 150-450 x 10⁹ /L), C-reactive protein level of 24.3 mg/L (RR, 0-10 mg/L), and serum calcium level of 3.31 mmol/L (RR, 2.18-2.58 mmol/L). Urinalysis demonstrated no pyuria, but 50 to 75 red blood cells per high-power field. Prothrombin time, activated partial thromboplastin time, and fibrinogen were within normal limits. An abdominal plain film revealed a mass lesion with a concealing right lower psoas shadow (Fig 1). Subsequent abdominal computed tomographic (CT) scan demonstrated a cyst-like lesion with irregular surface, involving adjacent tissues in the retroperitoneal cavity (Fig 2).

A CT-guided biopsy was performed because the discrepancy between clinical presentation and laboratory tests and image study made it difficult for physicians to discriminate psoas muscle abscess from malignancy. Ultimate pathology of biopsy specimens revealed a high-grade urothelial carcinoma with tumour necrosis. The TNM staging was stage IV (cT4N0M0). Blood and urine cultures were all negative. Follow-up 1 month later revealed a WBC count of 34.7 x 10⁹ /L.

Urothelial carcinoma originates in the urinary system. Paraneoplastic leukocytosis, defined by a WBC count of >20.0 x 10⁹ /L on more than two occasions 30 days apart, occurs in 0.6% of urothelial carcinoma cases.1 The aetiology of paraneoplastic leukocytosis is considered to be related to the production of granulocyte colony-stimulating factor by tumour cells.2 3 Hypercalcaemia, anaemia and thrombocytosis, as seen in this case, are also frequently seen in paraneoplastic syndrome. It is associated with advanced urothelial cancer and indicates a poor prognosis.1 3 Muscle invasion is also frequently found in cases of urothelial cancer with paraneoplastic leukocytosis.1 The cyst-like pattern of urothelial cancer on abdominal CT scan in combination with the paraneoplastic leukocytosis can mislead physicians into making an incorrect diagnosis, such as pyogenic psoas muscle abscess. We advise physicians to always be aware of urothelial cancer with paraneoplastic leukocytosis while managing a cyst-like lesion in the retroperitoneal cavity.

1. Izard JP, Gore JL, Mostaghel EA, Wright JL, Yu EY. Persistent, unexplained leukocytosis is a paraneoplastic syndrome associated with a poor prognosis in patients with urothelial carcinoma. Clin Genitourin Cancer 2015;13:e253-8. Crossref

2. Ito N, Matsuda T, Kakehi Y, Takeuchi E, Takahashi T, Yoshida O. Bladder cancer producing granulocyte colony-stimulating factor. N Engl J Med 1990;323:1709-10. Crossref

3. Kumar AK, Satyan MT, Holzbeierlein J, Mirza M, Van Veldhuizen P. Leukemoid reaction and autocrine growth of bladder cancer induced by paraneoplastic production of granulocyte colony-stimulating factor—a potential neoplastic marker: a case report and review of the literature. J Med Case Rep 2014;8:147. Crossref

A 53-year-old woman, menopausal for 4 years and with a previous kidney transplant presented with a 3-year history of excessive facial and body hair that required daily shaving in January 2008 (Fig 1). She had had no postmenopausal bleeding or gynaecological disease. She was prescribed immunosuppressants and corticosteroids but no hormones. There was no acne or hoarseness of voice. Examination revealed frontal balding and excessive hair over her chin, both shins, and lower abdomen with mild clitoromegaly. Serum testosterone was 19 nmol/L (reference range, 0.35-2.65 nmol/L); 17-hydroxyprogesterone (17-OHP) and dehydroepiandrosterone sulfate (DHEAS) levels were normal. Adrenocorticotropic hormone and cortisol levels were normal after overnight dexamethasone suppression test. Her follicle-stimulating hormone, luteinising hormone, thyroid-stimulating hormone, and prolactin levels were also normal. Serum oestradiol was in the premenopausal range (298 nmol/L). Transvaginal ultrasound showed a normal uterus with endometrial thickness of 5 mm and no adnexal masses.

Questions:

1. What are the differential diagnoses?

2. What further investigations are helpful?

3. How should the patient be managed?

Answers:

1. Androgen-secreting tumours of the ovary or adrenal gland.
Hirsutism involves excessive terminal hair growth in a masculine distribution in women. It can occur as a side-effect of immunosuppressants, eg cyclosporin with gingival hyperplasia and hirsutism. Nonetheless virilisation is uncommon. Cyclosporin should be changed to tacrolimus when hirsutism occurs.
Virilisation (development of male characteristics in women) occurs in less than 1% of patients with hirsutism. When it occurs (temporal hair recession and clitoromegaly in this patient) androgen-secreting tumours of the ovaries or adrenals should be suspected, particularly when onset is sudden with rapid progression.

2. Patients with virilisation should have serum testosterone, 17-OHP, and DHEAS checked. Serum testosterone level of >200 ng/dL (ie 6.94 nmol/L or 3 times normal) and/or DHEAS level of >700 µg/dL (ie 24.3 nmol/L) are indicative of virilising tumours.1 2 Computed tomography (CT) of the adrenals and pelvis should be considered. Ultrasonography of the pelvis may be difficult and not diagnostic in menopausal women because the ovaries are small and steroid-secreting tumours can be <1 cm in diameter.3 In this patient, normal levels of DHEAS and 17-OHP made adrenal tumour and congenital adrenal hyperplasia unlikely. Ovarian virilising tumours have to be suspected. Preoperative CT pelvis showed a 1-cm cyst in her right ovary.

3. Endometrial aspirate was performed, there was no hyperplasia or malignancy. She underwent laparotomy and bilateral salpingo-oophorectomy. There was a 1-cm yellowish tumour in the right ovary. The left ovary appeared normal. Hysterectomy was not done as the uterus was densely adhered to the bowel (history of peritoneal dialysis). Histology confirmed stromal luteoma and hyperthecosis in both ovaries without malignancy (Fig 2). After surgery, her testosterone level normalised. Hair re-grew over her frontal region and her body hair reduced.

Ovarian steroid cell tumours account for 0.1% to 0.2% of all ovarian tumours, and are composed of cells resembling steroid-secreting cells.4 Steroid cell tumours of small size and confined to the ovarian stroma are conventionally designated stromal luteomas and are usually associated with stromal hyperthecosis in adjacent stroma. They can have oestrogenic and/or androgenic manifestations with postmenopausal bleeding or virilisation, and are associated with endometrial hyperplasia or carcinoma.5 Hysterectomy and bilateral salpingo-oophorectomy is advised as some of these tumours may have malignant potential.

1. Somani N, Harrison S, Bergfeld WF. The clinical evaluation of hirsutism. Dermatol Ther 2008;21:376-91. Crossref

2. Hunter MH, Carek PJ. Evaluation and treatment of women with hirsutism. Am Fam Physician 2003;67:2565-72.

3. Outwater EK, Wagner BJ, Mannion C, McLarney JK, Kim B. Sex cord–stromal and steroid cell tumors of the ovary. Radiographics 1998;18:1523-46. Crossref

4. Hayes MC, Scully RE. Stromal luteoma of the ovary: a clinicopathological analysis of 25 cases. Int J Gynecol Pathol 1987;6:313-21. Crossref

5. Yamada S, Tanimoto A, Wang KY, Shimajiri S, Sasaguri Y. Stromal luteoma and nodular hyperthecosis of the bilateral ovaries associated with atypical endometrial hyperplasia of the uterus. Pathol Int 2009;59:831-3. Crossref

A 33-year-old Indian male was hospitalised for a 3-day history of headache and left lower limb weakness in December 2014. He had experienced no fever or seizures. He had visited New Delhi, India, the year before. Physical examination revealed the patient to be fully conscious with left lower limb monoparesis. There was no sensory deficit. Computed tomography (CT) revealed a superior parietal intra-axial lesion with a calcified focus (Fig 1a). Magnetic resonance imaging (MRI) delineated a 2 x 1.5 x 1.5 cm circumscribed hypointense cystic lesion with a contrast-enhancing wall and an eccentric intracystic signal with perilesional oedema (Figs 1b to 1d). Differential diagnoses included neurocysticercosis, brain abscess, brain metastasis, and malignant glioma. Craniotomy for excision was performed in view of the possibility of malignancy and the surgically accessible superficial location of the lesion. Intra-operatively, a firm capsular mass containing thick opaque material was seen (Fig 2a). Histology revealed a cysticercus within a fibrous capsule, compatible with the diagnosis of neurocysticercosis (Figs 2b and 2c). A 2-week course of oral albendazole was commenced and the patient was discharged with full recovery.

Neurocysticercosis is the most common parasitic infection of the central nervous system (CNS) caused by the larval form of Taenia solium. The peak age of incidence is between 25 and 35 years1 and the condition is endemic to the Indian subcontinent, coastal North Africa, sub-Saharan Africa, Latin America, and China. The main mode of transmission is by faecal-oral ingestion of tapeworm embryos.1 2 Consumption of contaminated poorly cooked pork is a less-frequent alternative source of infection since pigs are intermediate hosts.2 3 Within 72 hours of ingestion, larvae known as oncospheres are released and pass through the intestinal wall into the circulation, subsequently depositing in the CNS, retina, and skeletal muscle as cysticerci.1 2 The parasite can remain viable in the brain for several years after which it undergoes calcific degeneration.3 In endemic areas, the most common presentation is epilepsy, responsible for 30% of cases.1 Focal neurological deficits may occur including cranial nerve palsy due to basal meningitis. Obstructive hydrocephalus develops when lesions occupy the fourth ventricle.1 2

Characteristic radiological features include dystrophic calcification on CT imaging, cyst wall contrast enhancement on T1-weighted MRI and identification of the pathognomonic scolex, an eccentric focus of enhancement representing the tapeworm’s head, best delineated with fluid-attenuated inversion recovery sequences (hole-with-dot sign).3 4 Brain abscess or metastases are important differential diagnoses as they are also similarly located at the grey-white matter junction of the middle cerebral artery distribution, associated with disproportionately significant perilesional cerebral oedema and classically exhibit heterogeneous contrast enhancement. Malignant glioma was less likely in our patient since they are morphologically more infiltrative, and the present lesion was well-circumscribed. For this patient, the major distinguishing feature that supported a diagnosis of neurocysticercosis was the presence of dystrophic calcification on CT and, in retrospect, the presence of a scolex on MRI. Absolute criteria for a definitive diagnosis are either histological parasitic proof, imaging demonstration of a scolex, or subretinal parasites on fundoscopy (Table5). Serological enzyme-linked immunoelectrotransfer blot detection of anti-cysticercus antibodies or cerebrospinal fluid enzyme-linked immunosorbent assays are adjunctive investigations.1 6 Management of active neurocysticercosis includes antiepileptic drug administration, anti-inflammatory glucocorticoid therapy, and definitive antiparasitic therapy with albendazole (15 mg/kg per day) or praziquantel (50 mg/kg per day) for 2 to 4 weeks.1 Surgical excision is reserved for cysts that cause mass effect, hydrocephalus, or if the diagnosis is unclear.2

In an era of increasing migration and international travel, patients from developing countries who present with seizures, raised intracranial pressure symptoms, or focal neurological deficit should be suspected of having neurocysticercosis when characteristic imaging findings are identified. In probable cases, a trial of antiparasitic therapy is recommended with serial scans arranged to monitor treatment response.

1. Garcia HH, Nash TE, Del Brutto OH. Clinical symptoms, diagnosis, and treatment of neurocysticercosis. Lancet Neurol 2014;13:1202-15. Crossref

2. Zymberg ST. Neurocysticercosis. World Neurosurg 2013;79(2 Suppl):S24.e5-8.

3. Dhesi B, Karia SJ, Adab N, Nair S. Imaging in neurocysticercosis. Pract Neurol 2015;15:135-7. Crossref

4. Lerner A, Shiroishi MS, Zee CS, Law M, Go JL. Imaging of neurocysticercosis. Neuroimaging Clin N Am 2012;22:659-76. Crossref

5. Del Brutto OH, Rajshekhar V, White AC Jr, et al. Proposed diagnostic criteria for neurocysticercosis. Neurology 2001;57:177-83. Crossref

6. Gekeler F, Eichenlaub S, Mendoza EG, Sotelo J, Hoelscher M, Löscher T. Sensitivity and specificity of ELISA and immunoblot for diagnosing neurocysticercosis. Eur J Clin Microbiol Infect Dis 2002;21:227-9. Crossref

A middle-aged man admitted with abdominal pain and anaemia in December 2015. A computed tomographic (CT) angiogram demonstrated a superior indentation with focal narrowing in the proximal celiac axis (Fig 1). Conventional superior mesenteric arteriogram demonstrated prominent collaterals, and retrograde flow of contrast from the superior mesenteric artery (SMA) to the hepatic arteries (Fig 2). It was likely related to chronic compression of the proximal celiac artery. Low insertion of the median arcuate ligament (MAL) can be found in normal asymptomatic people. In this case, prominent collaterals and the retrograde flow from the SMA supported the diagnosis and may have explained his symptoms. In symptomatic cases, surgical division of the median arcuate ligament is the mainstay of treatment.

The MAL is a fibrous arch that unites the diaphragmatic crura on either side of the aortic hiatus. The crura pass superior and anterior to surround the aortic opening and to join the central tendon of the diaphragm. The ligament usually passes superior to the origin of the celiac axis. The insertion of the ligament may be low and therefore crossover the proximal portion of the celiac axis, causing a characteristic indentation. If it is significantly compressed on the celiac axis, this will compromise vascular flow and produce symptoms.

The MAL syndrome was first described in 1963 by Harjola1 and in 1965 by Dunbar et al.2 The definition of the syndrome relies on a combination of both clinical and radiographic features. Clinically, they described a classical triad of chronic postprandial abdominal pain, epigastric bruit, and weight loss.3 4 Extrinsic compression of the celiac trunk by the MAL occurs in 10% to 24% of patients.1 Usually, patients are asymptomatic and the classical triad is not always present, presumably due to collateral supply from the superior mesenteric circulation.1 2 The disease typically occurs in young patients and is more common in thin women who may present with epigastric pain and weight loss.1 The abdominal pain may be associated with eating, but not always.1 On physical examination, an abdominal bruit that varies with respiration may be audible in the mid-epigastric region. Symptoms are thought to arise from compression of the celiac axis with consequent compromised blood flow.

The diagnosis of celiac artery compression is traditionally made following conventional angiography. The use of thin-section multidetector CT and three-dimensional imaging techniques has greatly improved the ability to non-invasively obtain detailed images of the mesenteric vessels. Compression of the celiac axis by the MAL produces characteristic findings visible on CT angiography. Computed tomographic angiography can play a role in the diagnosis of this condition by demonstrating the characteristic focal narrowing of the celiac artery (Fig 1) with a hooked appearance that distinguishes this condition from other causes of celiac artery narrowing, such as atherosclerotic disease. Indentation of the origin of coeliac artery is exacerbated during the expiratory phase. Repeating CT on inspiration can often distinguish clinically significant narrowing from transient compression seen only during expiration in some patients, and is how most abdominal CT studies are performed.1

The majority of affected patients have no symptoms, thus radiographic finding of celiac axis compression alone may not be significant, unless it is correlated with clinical symptoms. Severe compression occurs in approximately 1% of patients.1 Severe stenosis will result in post-stenotic dilatation, and in some cases, the celiac axis will be fed by the SMA via the pancreaticoduodenal arcade. This was evident on the angiogram of our patient with prominent collaterals and retrograde flow from the SMA (Fig 2). His CT angiogram showed a characteristic hooked focal narrowing at the superior proximal celiac artery (Fig 1).

The surgical management of MAL syndrome is controversial.1 2 Surgical treatment in severe cases is advocated, particularly in cases with post-stenotic dilatation and collateral vessels (Fig 2), by division of the ligament. A laparoscopic approach is being increasingly adopted. Celiac angioplasty and stenting by endovascular means may be a future hot topic.2

1. Harjola PT. A rare obstruction of the coeliac artery: report of a case. Ann Chir Gynaecol Fenn 1963;52:547-50.

2. Dunbar JD, Molnar W, Beman FF, Marable SA. Compression of the celiac artery and abdominal angina. Am J Roentgenol Radium Ther Nucl Med 1965;95:731-44. Crossref

3. Horton KM, Talamini MA, Fishman EK. Median arcuate ligament syndrome: evaluation with CT angiography. Radiographics 2005;25:1177-82. Crossref

4. Duffy AJ, Panait L, Eisenberg D, Bell RL, Roberts KE, Sumpio B. Management of median arcuate ligament syndrome: a new paradigm. Ann Vasc Surg 2009;23:778-84. Crossref