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Abstract
A 28-year-old woman came for non-traumatic right flank pain with hypotension and right flank mass. She had multiple hyperpigmented skin papules located on the centre area of her face, and angiomas on her toes. She was anaemic and had a blood transfusion on top of aggressive fluid resuscitation. Abdominal CT showed bilaterally enlarged kidneys and fluid collection in the right perirenal space (haemorrhage). The consideration was an angiomyolipoma in spontaneous perinephric haemorrhage. We considered tuberous sclerosis complex (TSC) and did genetic testing. Results revealed mutations in the TSC2 gene, consistent with the diagnosis of TSC. No immediate surgical plans were considered at that time. She opted to be discharged against medical advice and was scheduled for a close outpatient follow-up. The patient followed up after 2 weeks, already on sirolimus 2 mg once daily. She reported improved overall well-being and a decrease in the flank mass size.
- genetic screening / counselling
- gene therapy
- oncology
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Background
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with a prevalence of approximately 1 to 6000–12 000 worldwide. It affects nearly all organ systems.1 Prominent features include adenoma sebaceum, glial tumours, rhabdomyoma (especially of the heart) and hamartomatous tumours in the following: thyroid, retina, liver, pancreas, lung, kidney, adrenals and ovaries.2 The different manifestations of TSC depend on organs affected such as, but not limited to, the brain, kidneys, skin, heart and lungs.3
Renal angiomyolipoma (AML) is a benign hamartoma that occurs in patients with TSC. It is estimated that 80% of patients with TSC will also have another hamartoma2; renal AML that is associated with TSC is only 0.3% of all renal neoplasms.4 Simply, renal AML is common in patients with TSC but extremely rare in the general population.5 Renal AML associated with TSC is usually bilateral and multifocal, and more likely to be life-threatening due to a greater propensity to develop haemorrhage as compared with an isolated renal AML.6
One of the feared complications of renal AML is haemorrhage, and a rare condition associated with it is the Wünderlich syndrome (WS). This occurs when there is atraumatic renal haemorrhage into the subcapsular and perirenal spaces. Common aetiologies of WS are renal tumours (benign and malignant) such as AMLs and renal cell carcinoma (RCC), vascular lesions and infection. WS also manifests with Lenk’s triad: flank pain, abdominal mass and shock (hypovolaemia). The diagnostic test of choice is a CT with contrast. Management is expectant; more invasive procedures, such as endovascular embolisation or urgent surgery (partial nephrectomy, radical nephrectomy or evacuation of a haematoma), are done on a case-to-case basis, especially in patients with massive haemorrhage.7 8
Here, we present a case of a patient who presented with the cutaneous features of TSC with bilateral renal AML in WS but remained undiagnosed all her life.
Case presentation
A 28-year-old woman came in the emergency department for right flank pain lasting 4 hours with no history of trauma. She previously consulted another hospital where a whole abdominal ultrasound was done, revealing a complex retroperitoneal mass on the right measuring 14.9×9.3×14 cm. She was then advised urologic evaluation and transferred to our institution. She had no dysuria, hypogastric pain nor haematuria. She was of Filipino descent and was the eldest among 12 siblings (figure 1). Since childhood, she had multiple hyperpigmented skin papules on the central face and an erythematous plaque on the left side of the face. Her highest educational attainment was grade 5 of elementary school; she was not promoted and, therefore, dropped out. Her obstetric score was G1P1 (1001).
The three-generation pedigree of the patient. The females are represented by circles and males by squares. The barred circle represents the deceased female. Affected individuals are represented with solid symbols (ie, circle which represents the patient). The index patient is represented by a solid circle with an arrow.
Physical examination revealed pale palpebral conjunctivae. No lymphadenopathies were noted. She had multiple hyperpigmented skin papules located on the central area of her face, fibrous cephalic plaques, an erythematous plaque at the left upper quadrant, periungual angiomas and angiofibroma (figure 2). Her abdomen was enlarged but was not oedematous; fluid wave was not observed. Incidentally, a right flank mass (doughy, round, non-tender) measuring 7.6 cm×7.6 cm was palpated. The rest of her physical examination was unremarkable.
(Top to bottom; left to right) Multiple hyperpigmented skin papules, fibrous cephalic plaques, an erythematous plaque at the left upper quadrant, periungual angiomas and angiofibroma.
On admission, she was hypotensive (blood pressure of 80/50 mm Hg) and anaemic (haemoglobin of 46 g/L). This necessitated fluid resuscitation and was transfused with packed red cells. The patient’s blood pressure then rose to 110/70 mm Hg. The rest of her blood and urine laboratory tests, as well as the 12 lead ECG and chest X-ray, were all unremarkable. Her previously noted retroperitoneal mass was also investigated further and she underwent a CT scan of the abdomen with contrast. Furthermore, she was referred to the interventional radiology service for an ultrasound-guided aspiration biopsy of the mass. However, on the consideration of an AML based on the CT, the biopsy was deferred due to the possibility of puncturing blood vessels. At this point, the service considered the patient to be a case of tuberous sclerosis, and she was referred to the genetics service. Genetic testing was done for 47 genes using a saliva sample.
The result revealed a TSC2 gene mutation, consistent with the diagnosis of tuberous sclerosis. This strengthened our evidence that the renal mass was an AML. Furthermore, with the presentation of hypovolaemic shock, right flank mass and right flank pain (Lenk’s Triad), we diagnosed her to be in WS. No immediate surgical plans were considered at that time by the urology team due to the patient being asymptomatic, haemodynamically stable and did not consent to any invasive procedures.
Investigations
Abdominal CT with triple contrast revealed that both kidneys were enlarged with innumerable, confluent, ill-to-fairly defined mixed hypoattenuating, fat-containing, heterogeneously enhancing masses of varying sizes arising from the renal parenchyma. The renal parenchyma appeared to be irregular while the masses exhibited marked enhancement on contrast study, with blood supply coming from multiple prominent, tortuous renal vessels. There was a non-enhancing, hyperdense fluid collection occupying the right perirenal space. The collection had an approximate volume of 611 mL and was considered to be a haemorrhage (figure 3). There was also generalised, segmental thickening of the walls of the small and large bowel loops. The rest of the abdominal and pelvic structures were unremarkable. Echocardiography with Doppler studies, cranial and chest CT with contrast were all unremarkable.
(Left to right) Coronal view of abdominopelvic CT scan with triple contrast showing (A) fluid collection approximately 611 mL at the right perirenal space; and (B) both kidneys are enlarged with tortuous renal vessels and hypoattenuating, fat-containing masses (angiomyolipomas).
Next-generation sequencing was conducted using the Invitae Common Hereditary Cancers Panel, which involved 47 genes from a saliva sample. Results identified a loss-of-function variant, c.894dup (p.Val299Cysfs*39), in one allele of the TSC2 gene. This sequence change creates a premature translational stop signal, leading to an absent or disrupted protein product that is consistent with TSC. Also, a variant of uncertain significance, c.2276G>A (p.Arg759His), was identified in the POLE gene (table 1).
Molecular picture of the gene mutations reported by Invitae
Differential diagnosis
One of the considerations at the time (regarding the renal mass) was RCC. However, RCCs are rarely bilateral and would often present with telltale signs such as haematuria. On admission, the abdominal CT scan revealed fat on the renal masses. The consideration of RCC was then deemed unlikely, and we then shifted to AML as the strongest primary consideration. Although sporadic AMLs are more common than the ones associated with TSC, the patient presented with multiple cutaneous lesions that are diagnostic of TSC. With the demonstration of a TSC 2 mutation and the consideration of AML based on imaging, our working impression of TSC was further strengthened.
Treatment
Blood was transfused to address the patient’s anaemia. She was seen by the genetics service and was counselled regarding her genetic condition. Her immediate family also had genetic counselling. She opted to go home against medical advice and to continue her care at the outpatient clinic. She also verbalised that she planned to seek consultation with a private medical oncologist. Her condition was explained again, a copy of her laboratory and imaging results were given to her, and her case was endorsed to the private physician mentioned earlier.
Outcome and follow-up
The patient followed up at the outpatient clinic after 2 weeks. She was on sirolimus 2 mg once daily as prescribed by her medical oncologist. At this time, abdominal pain had resolved, her right flank mass was noted to have decreased in size and she reported improved overall well-being. Her blood pressure on follow-up was 110/80 mm Hg. She was scheduled for a repeat abdominal CT scan with triple contrast after 5 months (approximately 6 months since the first abdominal CT scan with triple contrast) which then revealed the fluid collection to be estimated at 100 mL (figure 4), from 611 mL 6 months ago. She then requested to continue her follow-up with her private doctor for convenience (closer to her residence).
Coronal view of the abdominopelvic CT scan with triple contrast showing a decrease in the fluid collection now approximately 100 mL at the right perirenal space with the previously noted masses to be decreased in size.
Discussion
TSC is an autosomal dominant disease. As much as 60% of those with TSC have no family history of the condition.9 The clinical manifestations of TSC depend on the target organ or organs affected and the extent of damage brought about by the lesions.10
AML is a benign renal neoplasm composed of fat, vascular and smooth muscle tissues. The most important association of this is with TSC.11
The average size of AML associated with tuberous sclerosis is around 9.6±4.8 cm, and in those without tuberous sclerosis is around 4.1±3.4 cm, as reported in the study conducted by Steiner et al.12 AMLs may extend into the perirenal space and may arise from the renal parenchyma.13 Our patient was diagnosed at 28 years old after presenting with right upper quadrant pain.
The diagnosis of AML can be done using imaging, either by CT or by magnetic resonance.14 The incidence of having fat-containing RCC is negligible that it does not pose a diagnostic dilemma.15 16 In this case, the diagnosis of AML was done by the abdominal CT scan findings.
In managing AMLs, therapeutic intervention is recommended in certain cases such as the presence of symptoms, large lesions, women of childbearing age and poor access to follow-up or emergency care. Until now, there is no certain tumour size being recommended to initiate treatment.17 However, for patients who are asymptomatic with AMLs bigger than 3 cm, mammalian Target of Rapamycin (mTOR) inhibitors are the suggested first-line treatment and are shown to be most effective and superior compared with other treatment modalities.18 The interventional radiology and urology services opted not to do invasive interventions on the patient. Instead, she was started on sirolimus, an mTOR inhibitor. Sirolimus interrupts tumour progression and promotes the reversion of existing lesions by regulating the Phosphatidylinositol 3-kinase/Serine/Threonine Protein-specific kinase/mammalian Target of Rapamycin (PI3K/Akt/mTOR) pathway.19 In early studies, sirolimus was well tolerated; skin lesions, oral ulcers, proteinuria and dyslipidaemia were commonly encountered side effects.20
WS is characterised by non-traumatic renal haemorrhage confined to the subcapsular and/or perirenal areas. This is a rare condition with only 250 cases reported worldwide. The management of this condition is mainly expectant, with the use of more invasive procedures such as endovascular embolisation and nephrectomy done on a case-to-case basis.7 Since the patient’s offspring have the potential of becoming carriers of TSC2 and POLE mutations, implications of these events require a thorough discussion with the patient. The importance of genetic counselling cannot be overemphasised. To our knowledge, there are only a few published case reports on people with TSC-associated bilateral and large AMLs. And this is the first case report on a person showing TSC2 and POLE gene mutations.
Patient’s perspective
I didn’t know what was happening to me. All my life I grew up with these ‘skin tags’ on my face and was failing every subject back in elementary. My sister also had it, so we thought it was a normal birthmark. This year, ever since I noticed the pain in my right flank and my abdomen was growing; I have been seeing doctors. Blood was extracted multiple times and even got an x-ray and CT-scan. I was told that I was right, the ‘skin tags’ on my face was a hereditary feature, but it was not normal. It meant that I had genes different from other healthy individuals. I was also counseled on what the complications of my disease are as well as how it could also afflict my children. I know have a better understanding and grasp of it, so I will follow-up with my doctor. I will also bring my sister and children for genetic counseling.
Learning points
In young females (especially those of Southeast Asian descent) presenting with multiple dermatological lesions along with multiple renal masses and development delay, tuberous sclerosis complex (TSC) should be considered.
Since TSC is an autosomal dominant disorder, it is important to obtain a thorough family history, screen relatives and do genetic counselling.
Early recognition could lead to the prevention of fatal complications from this disease at the adult stage.
In terms of management, there is room for a conservative approach.
The POLE gene alteration might be present among patients diagnosed with TSC.
Ethics statements
References
Footnotes
Contributors RBL: Responsible for the care of the patient and principal author of the paper. HHCC: Senior coauthor who helped revise the manuscript. DLS: Consultant coauthor who helped revise the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.