RESEARCH ARTICLE
Lymphedema in Tuberous Sclerosis Complex Alexandra L. Geffrey,1 Julianna E. Shinnick,1 Brigid A. Staley,1 Susana Boronat,1,2 and Elizabeth A. Thiele1* 1
Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts Department of Pediatric Neurology, Vall d’Hebron Hospital, Universitat Auto`noma de Barcelona, Barcelona, Spain
2
Manuscript Received: 30 May 2013; Manuscript Accepted: 6 January 2014
Congenital lymphedema has been described as a possible rare association of tuberous sclerosis complex (TSC), with only six previous cases reported in the literature. TSC is an autosomal dominant, multisystem disorder connected to aberrant regulation of the mammalian target of rapamycin (mTOR) pathway. The aim of this study is to review cases of lymphedema in a large cohort of TSC patients. The medical records of 268 patients seen at The Herscot Center for Children and Adults with Tuberous Sclerosis Complex at the Massachusetts General Hospital from 2002 to 2012 were retrospectively reviewed for reports of lymphedema or edema of unknown etiology. Genotypic and phenotypic data were collected in accordance with institutional review board (IRB) approval. This cohort presents two new cases of congenital lymphedema in TSC patients and acquired lymphedema was found in eight additional cases. Thus, we report 10 new cases of lymphedema in TSC (4%). The two patients with congenital lymphedema were female, as were the previous six reported cases. The frequency of lymphedema reported here (4%) is higher than the estimated prevalence in the general population (0.133– 0.144%), suggesting a higher frequency of lymphedema in TSC. This study shows that patients with TSC and lymphedema are more likely to be females with renal AMLs and suggests that congenital lymphedema is a gender-specific (female) manifestation of TSC. Exploration of the potential role of mTOR antagonists may be important in treatment of lymphedema in TSC patients. Ó 2014 Wiley Periodicals, Inc.
Key words: edema; lymphatic abnormalities; lymphedema; tuberous sclerosis complex
How to Cite this Article: Geffrey AL, Shinnick JE, Staley BA, Boronat S, Thiele EA. 2014. Lymphedema in tuberous sclerosis complex. Am J Med Genet Part A 164A:1438–1442.
Prato et al., 2013]. Incidence is estimated to be approximately 1 in 6,000. It is caused by mutations in tumor suppressor genes TSC1 or TSC2, whose protein products hamartin and tuberin function as negative regulators in the mammalian target of rapamycin (mTOR) signaling pathway. Hamartin and tuberin form a physical and functional complex in which tuberin functions as the catalytic subunit to promote GTP hydrolysis of Rheb, the major downstream target of the Tsc1/Tsc2 complex, and hamartin interacts with tuberin through its coiled-coil domain to stabilize tuberin. A mutation in TSC1 or TSC2 leaves mTOR constitutively active and thus leads to a concomitant block of Akt signaling to its other downstream targets, resulting in uncontrolled proliferation, differentiation, and migration of cells. The TSC2 genotype typically results in a more severe phenotype, including a greater likelihood of developmental delays and more severe organ involvement [Dabora et al., 2001]. Lymphedema has traditionally been defined as a chronic condition characterized by interstitial edema and protein accumulation due to a defect in lymphatic drainage [Jensen et al., 2010]. Its estimated prevalence in the general population is 1.33–1.44 in 1,000 people [Moffatt et al., 2003; Williams et al., 2005]. Primary lymphedema is caused by developmental abnormalities of the lymphatic system [Mortimer et al., 1995; Connell et al., 2010] and affects
INTRODUCTION Congenital lymphedema has been described as a possible rare association of tuberous sclerosis complex (TSC) [Voudris et al., 2003] and there are only six published case reports of congenital lymphedema in patients with TSC [Cottafava et al., 1986; Hirsch et al., 1999; Voudris et al.,2003; Lucas et al., 2011; Sukulal et al., 2012]. The frequency of congenital lymphedema in TSC is unknown; acquired lymphedema has not previously been described in TSC. TSC is an autosomal dominant, multisystem disorder characterized by benign hamartomas in multiple organ systems, including the skin, brain, heart, kidneys, lungs, and eyes [Leung et al., 2007;
Ó 2014 Wiley Periodicals, Inc.
Conflict of interest: none. Alexandra L. Geffrey and Julianna E. Shinnick are co-first authors. Grant sponsor: Herscot Center for Tuberous Sclerosis Complex; Grant sponsor: NIH/NINDS; Grant number: P01 NS024279. Correspondence to: Elizabeth A. Thiele, M.D., Ph.D., The Herscot Center for Tuberous Sclerosis Complex, 175 Cambridge Street, Suite 340, Boston, MA 02114. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 25 March 2014 DOI 10.1002/ajmg.a.36469
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GEFFREY ET AL.
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approximately 1.15 in 100,000 people under the age of 20 years old [Smeltzer et al., 1985; Connell et al., 2010]. Primary lymphedema is typically classified by age of onset/diagnosis: congenital lymphedema is noted at birth or in the first year of life, lymphedema praecox is noted between the ages of 1 and 35 years, and lymphedema tarda is noted after 35 years of age. A more recent classification distinguishes congenital lymphedema when the onset is before 1 year of age and late onset when the clinical manifestations begin after 1 year of age [Connell et al., 2010]. Secondary lymphedema is caused by damage to the lymphatic system [Jensen et al., 2010] due to radiation, surgery, neoplasm, or infection [Smeltzer et al., 1985; Connell et al., 2010]. Edema is any abnormal build-up of fluid in tissues or the accumulation of excess interstitial fluids and can be caused by capillary filtration overwhelming lymph drainage and venous insufficiency [Topham et al., 2002]. Not all edema is lymphedema and pathology is not always easily determined. Pitting, or depression following deliberate pressure on the tissue, pushing lymph outside the indentation, is often but not always associated with lymphedema, depending on the stage of lymphedema [International Society of Lymphology, 1985] and can also be present in edema due to venous insufficiency. The Kaposi-Stemmer sign (failure to pinch a fold of skin at the base of the second toe) is considered pathognomonic of lymphedema [Connell et al., 2010]. This study reports two additional patients with TSC and congenital lymphedema, as well as eight patients with probable lymphedema.
MATERIALS AND METHODS The medical records of 268 patients seen at The Herscot Center for Children and Adults with Tuberous Sclerosis Complex at the Massachusetts General Hospital from January 2002 to August 2012 were retrospectively reviewed. Patients with lymphedema were identified. Clinical details regarding this condition, such as the presence of Kaposi-Stemmer sign or the presence of pitting edema, were recorded if the information was available in their records. Protein and albumin levels were recorded. Genotypic,
phenotypic, and clinical data were collected for each case in accordance with institutional review board (IRB) approval. Data about family history of lymphedema or dysmorphic features suggestive of other syndromes with primary lymphedema were searched. Sample size was too small to conduct binomial tests to measure significant differences between this cohort and the general TSC or lymphedema population. Gender ratios in the general TSC population were determined reviewing the same medical records of 268 patients seen at The Herscot Center. All patients reported had a diagnosis of definite TSC.
RESULTS Lymphedema was reported in 4% (10 [6 females, 4 males] of 268) of patients with TSC. The clinical findings in the two patients with congenital lymphedema are depicted in Table I along with the six previously reported cases (Patients A–F) [Cottafava et al., 1986; Hirsch et al., 1999; Voudris et al., 2003; Lucas et al., 2011; Sukulal et al., 2012; Prato et al., 2013]. Seven patients were diagnosed with lymphedema at a young age (before 38 years of age). One patient was considered to have probable lymphedema in both legs as it started at 60 years of age at which time venous insufficiency may also play a role in the etiology of the edema (Table II). Of note, 78% of our patients with lymphedema and TSC with genetic testing had TSC2 mutations (7/9). Of patients in this cohort, 80% had renal angiomyolipomas (AMLs) (8/10). One of the four adult females and one of the three adult males had lymphangiomyomatosis (LAM) (20%). No abdominal lymphadenopathy was found by imaging in any of the patients. The presence of pitting edema was determined in three patients but this information was not detailed in the rest and the presence of Kaposi-Stemmer sign was not recorded in any of the charts; all resisted postural or physical measures when tested. Plasma protein and albumin levels were measured in nine patients and were normal in all. Two of the four males had hydrocele in addition to lymphedema in both legs. Lymphoscintigraphy was not available for our patients. None of the reported patients were related; family history of lymphedema,
TABLE I. Congenital Lymphedema in TSC: Two Cases and Previous Cases in the Literature Patient A B C D E F
Tests for lymphedema evaluation
Age 7 28 5 1 0 4
Gender F F F F F F
Location Left leg Left leg Left leg Right leg Left leg Left upper limb
Mutation ND ND ND TSC1 ND TSC2 (del E1)
LAM No No No No No No
Renal AML ND ND No Yes No Yes
G
8
F
TSC2 (c.501G>A; p.W167X)
No
No
H
15
F
Left leg extending to left buttock and lower abdomen Left leg, ankle
Radiograph and MRI of left arm, echo-color-Doppler ultrasonography (normal) MRI of pelvis and leg
TSC2 (del E13-19)
No
Yes
No
Reference Cottafava et al. (1986) Hirsch et al. (1999) Voudris et al. (2003) Lucas et al. (2011) Sukulal et al. (2012) Prato et al. (2013)
Current study
Current study
ND ND Scrotal ultrasonography ND ND
dysmorphic features, or malformation unrelated to their TSC and consanguinity of parents were not reported. The congenital lymphedema of Patient G (Table I) was evaluated by MRI at 10 months of age, which showed findings consistent with diffuse mixed venous-lymphatic malformation and normal patency of the deep venous system of the left lower extremity. At age 5, the patient’s left leg ranged from 1.36 to 1.55 times the size of her right (measuring circumference at consistent sites on thigh and calf). The patient had difficulty with strenuous activity and received occupational and physical therapy. At 7 years of age she was started on rapamycin, 4 mg once a day, which was increased to 8 mg after 6 weeks. Within several months of rapamycin treatment, the circumference of her leg decreased significantly although the MRI showed no significant changes in the imaging of the lymphatic malformation. Ankle and foot involvement also improved, and individual toes and toenails could be distinguished. Rapamycin treatment also led to a decrease in size and extent of dermatologic features including facial forehead plaques and angiofibroma. Initially she tolerated the rapamycin well, with only occasional mouth ulcers, a common side effect of the rapamycin, but after many months, medication was discontinued due to recurrent viral illnesses. Subsequently, the size of her leg and foot returned within several weeks to pretreatment size.
Yes Yes No Yes Yes ND ND Yes Yes ND
Lymphedema in Tuberous Sclerosis Complex Alexandra L. Geffrey,1 Julianna E. Shinnick,1 Brigid A. Staley,1 Susana Boronat,1,2 and Elizabeth A. Thiele1* 1
Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts Department of Pediatric Neurology, Vall d’Hebron Hospital, Universitat Auto`noma de Barcelona, Barcelona, Spain
2
Manuscript Received: 30 May 2013; Manuscript Accepted: 6 January 2014
Congenital lymphedema has been described as a possible rare association of tuberous sclerosis complex (TSC), with only six previous cases reported in the literature. TSC is an autosomal dominant, multisystem disorder connected to aberrant regulation of the mammalian target of rapamycin (mTOR) pathway. The aim of this study is to review cases of lymphedema in a large cohort of TSC patients. The medical records of 268 patients seen at The Herscot Center for Children and Adults with Tuberous Sclerosis Complex at the Massachusetts General Hospital from 2002 to 2012 were retrospectively reviewed for reports of lymphedema or edema of unknown etiology. Genotypic and phenotypic data were collected in accordance with institutional review board (IRB) approval. This cohort presents two new cases of congenital lymphedema in TSC patients and acquired lymphedema was found in eight additional cases. Thus, we report 10 new cases of lymphedema in TSC (4%). The two patients with congenital lymphedema were female, as were the previous six reported cases. The frequency of lymphedema reported here (4%) is higher than the estimated prevalence in the general population (0.133– 0.144%), suggesting a higher frequency of lymphedema in TSC. This study shows that patients with TSC and lymphedema are more likely to be females with renal AMLs and suggests that congenital lymphedema is a gender-specific (female) manifestation of TSC. Exploration of the potential role of mTOR antagonists may be important in treatment of lymphedema in TSC patients. Ó 2014 Wiley Periodicals, Inc.
Key words: edema; lymphatic abnormalities; lymphedema; tuberous sclerosis complex
How to Cite this Article: Geffrey AL, Shinnick JE, Staley BA, Boronat S, Thiele EA. 2014. Lymphedema in tuberous sclerosis complex. Am J Med Genet Part A 164A:1438–1442.
Prato et al., 2013]. Incidence is estimated to be approximately 1 in 6,000. It is caused by mutations in tumor suppressor genes TSC1 or TSC2, whose protein products hamartin and tuberin function as negative regulators in the mammalian target of rapamycin (mTOR) signaling pathway. Hamartin and tuberin form a physical and functional complex in which tuberin functions as the catalytic subunit to promote GTP hydrolysis of Rheb, the major downstream target of the Tsc1/Tsc2 complex, and hamartin interacts with tuberin through its coiled-coil domain to stabilize tuberin. A mutation in TSC1 or TSC2 leaves mTOR constitutively active and thus leads to a concomitant block of Akt signaling to its other downstream targets, resulting in uncontrolled proliferation, differentiation, and migration of cells. The TSC2 genotype typically results in a more severe phenotype, including a greater likelihood of developmental delays and more severe organ involvement [Dabora et al., 2001]. Lymphedema has traditionally been defined as a chronic condition characterized by interstitial edema and protein accumulation due to a defect in lymphatic drainage [Jensen et al., 2010]. Its estimated prevalence in the general population is 1.33–1.44 in 1,000 people [Moffatt et al., 2003; Williams et al., 2005]. Primary lymphedema is caused by developmental abnormalities of the lymphatic system [Mortimer et al., 1995; Connell et al., 2010] and affects
INTRODUCTION Congenital lymphedema has been described as a possible rare association of tuberous sclerosis complex (TSC) [Voudris et al., 2003] and there are only six published case reports of congenital lymphedema in patients with TSC [Cottafava et al., 1986; Hirsch et al., 1999; Voudris et al.,2003; Lucas et al., 2011; Sukulal et al., 2012]. The frequency of congenital lymphedema in TSC is unknown; acquired lymphedema has not previously been described in TSC. TSC is an autosomal dominant, multisystem disorder characterized by benign hamartomas in multiple organ systems, including the skin, brain, heart, kidneys, lungs, and eyes [Leung et al., 2007;
Ó 2014 Wiley Periodicals, Inc.
Conflict of interest: none. Alexandra L. Geffrey and Julianna E. Shinnick are co-first authors. Grant sponsor: Herscot Center for Tuberous Sclerosis Complex; Grant sponsor: NIH/NINDS; Grant number: P01 NS024279. Correspondence to: Elizabeth A. Thiele, M.D., Ph.D., The Herscot Center for Tuberous Sclerosis Complex, 175 Cambridge Street, Suite 340, Boston, MA 02114. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 25 March 2014 DOI 10.1002/ajmg.a.36469
1438
GEFFREY ET AL.
1439
approximately 1.15 in 100,000 people under the age of 20 years old [Smeltzer et al., 1985; Connell et al., 2010]. Primary lymphedema is typically classified by age of onset/diagnosis: congenital lymphedema is noted at birth or in the first year of life, lymphedema praecox is noted between the ages of 1 and 35 years, and lymphedema tarda is noted after 35 years of age. A more recent classification distinguishes congenital lymphedema when the onset is before 1 year of age and late onset when the clinical manifestations begin after 1 year of age [Connell et al., 2010]. Secondary lymphedema is caused by damage to the lymphatic system [Jensen et al., 2010] due to radiation, surgery, neoplasm, or infection [Smeltzer et al., 1985; Connell et al., 2010]. Edema is any abnormal build-up of fluid in tissues or the accumulation of excess interstitial fluids and can be caused by capillary filtration overwhelming lymph drainage and venous insufficiency [Topham et al., 2002]. Not all edema is lymphedema and pathology is not always easily determined. Pitting, or depression following deliberate pressure on the tissue, pushing lymph outside the indentation, is often but not always associated with lymphedema, depending on the stage of lymphedema [International Society of Lymphology, 1985] and can also be present in edema due to venous insufficiency. The Kaposi-Stemmer sign (failure to pinch a fold of skin at the base of the second toe) is considered pathognomonic of lymphedema [Connell et al., 2010]. This study reports two additional patients with TSC and congenital lymphedema, as well as eight patients with probable lymphedema.
MATERIALS AND METHODS The medical records of 268 patients seen at The Herscot Center for Children and Adults with Tuberous Sclerosis Complex at the Massachusetts General Hospital from January 2002 to August 2012 were retrospectively reviewed. Patients with lymphedema were identified. Clinical details regarding this condition, such as the presence of Kaposi-Stemmer sign or the presence of pitting edema, were recorded if the information was available in their records. Protein and albumin levels were recorded. Genotypic,
phenotypic, and clinical data were collected for each case in accordance with institutional review board (IRB) approval. Data about family history of lymphedema or dysmorphic features suggestive of other syndromes with primary lymphedema were searched. Sample size was too small to conduct binomial tests to measure significant differences between this cohort and the general TSC or lymphedema population. Gender ratios in the general TSC population were determined reviewing the same medical records of 268 patients seen at The Herscot Center. All patients reported had a diagnosis of definite TSC.
RESULTS Lymphedema was reported in 4% (10 [6 females, 4 males] of 268) of patients with TSC. The clinical findings in the two patients with congenital lymphedema are depicted in Table I along with the six previously reported cases (Patients A–F) [Cottafava et al., 1986; Hirsch et al., 1999; Voudris et al., 2003; Lucas et al., 2011; Sukulal et al., 2012; Prato et al., 2013]. Seven patients were diagnosed with lymphedema at a young age (before 38 years of age). One patient was considered to have probable lymphedema in both legs as it started at 60 years of age at which time venous insufficiency may also play a role in the etiology of the edema (Table II). Of note, 78% of our patients with lymphedema and TSC with genetic testing had TSC2 mutations (7/9). Of patients in this cohort, 80% had renal angiomyolipomas (AMLs) (8/10). One of the four adult females and one of the three adult males had lymphangiomyomatosis (LAM) (20%). No abdominal lymphadenopathy was found by imaging in any of the patients. The presence of pitting edema was determined in three patients but this information was not detailed in the rest and the presence of Kaposi-Stemmer sign was not recorded in any of the charts; all resisted postural or physical measures when tested. Plasma protein and albumin levels were measured in nine patients and were normal in all. Two of the four males had hydrocele in addition to lymphedema in both legs. Lymphoscintigraphy was not available for our patients. None of the reported patients were related; family history of lymphedema,
TABLE I. Congenital Lymphedema in TSC: Two Cases and Previous Cases in the Literature Patient A B C D E F
Tests for lymphedema evaluation
Age 7 28 5 1 0 4
Gender F F F F F F
Location Left leg Left leg Left leg Right leg Left leg Left upper limb
Mutation ND ND ND TSC1 ND TSC2 (del E1)
LAM No No No No No No
Renal AML ND ND No Yes No Yes
G
8
F
TSC2 (c.501G>A; p.W167X)
No
No
H
15
F
Left leg extending to left buttock and lower abdomen Left leg, ankle
Radiograph and MRI of left arm, echo-color-Doppler ultrasonography (normal) MRI of pelvis and leg
TSC2 (del E13-19)
No
Yes
No
Reference Cottafava et al. (1986) Hirsch et al. (1999) Voudris et al. (2003) Lucas et al. (2011) Sukulal et al. (2012) Prato et al. (2013)
Current study
Current study
ND ND Scrotal ultrasonography ND ND
dysmorphic features, or malformation unrelated to their TSC and consanguinity of parents were not reported. The congenital lymphedema of Patient G (Table I) was evaluated by MRI at 10 months of age, which showed findings consistent with diffuse mixed venous-lymphatic malformation and normal patency of the deep venous system of the left lower extremity. At age 5, the patient’s left leg ranged from 1.36 to 1.55 times the size of her right (measuring circumference at consistent sites on thigh and calf). The patient had difficulty with strenuous activity and received occupational and physical therapy. At 7 years of age she was started on rapamycin, 4 mg once a day, which was increased to 8 mg after 6 weeks. Within several months of rapamycin treatment, the circumference of her leg decreased significantly although the MRI showed no significant changes in the imaging of the lymphatic malformation. Ankle and foot involvement also improved, and individual toes and toenails could be distinguished. Rapamycin treatment also led to a decrease in size and extent of dermatologic features including facial forehead plaques and angiofibroma. Initially she tolerated the rapamycin well, with only occasional mouth ulcers, a common side effect of the rapamycin, but after many months, medication was discontinued due to recurrent viral illnesses. Subsequently, the size of her leg and foot returned within several weeks to pretreatment size.
Yes Yes No Yes Yes ND ND Yes Yes ND
