Pik3ca-Related Segmental Overgrowth
Summary
Clinical characteristics.
PIK3CA-associated segmental overgrowth includes disorders of brain (e.g., MCAP [megalencephaly-capillary malformation] syndrome, hemimegalencephaly); and segmental body overgrowth (e.g., CLOVES [congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies] syndrome, fibroadipose hyperplasia [FH]). Heterozygous (usually somatic mosaic) pathogenic variants of PIK3CA are causative.
MCAP syndrome is characterized by the major findings of (1) megalencephaly (MEG) or hemimegalencephaly (HMEG) associated with neurologic findings of hypotonia, seizures, and mild to severe intellectual disability; and (2) cutaneous capillary malformations with focal or generalized somatic overgrowth. Additional findings can include digital anomalies (syndactyly, polydactyly), cortical malformations – most distinctively polymicrogyria (PMG); and variable connective tissue dysplasia.
CLOVES (or CLOVE) syndrome and fibroadipose hyperplasia (FH) may be associated with (1) MEG or HMEG; and (2) patchy segmental overgrowth associated with skeletal anomalies, lipomatosis, vascular malformations, and epidermal nevi.
Diagnosis/testing.
PIK3CA-associated segmental overgrowth is confirmed in an individual with a pathogenic variant on one PIK3CA allele, typically in affected tissues. Because the vast majority of PIK3CA pathogenic variants arise postzygotic (and are thus mosaic), more than one tissue may need to be tested. Failure to detect a PIK3CA pathogenic variant does not exclude a clinical diagnosis of the PIK3CA-associated segmental overgrowth disorders in individuals with suggestive features.
Management.
Treatment of manifestations: Significant or lipomatous segmental overgrowth may require debulking; scoliosis and leg-length discrepancy may require orthopedic care and surgical intervention. Neurologic complications (e.g., obstructive hydrocephalus, increased intracranial pressure, progressive and/or symptomatic cerebellar tonsillar ectopia or Chiari malformation; epilepsy in those with HMEG) may warrant neurosurgical intervention. Routine treatment of the following, when present, is indicated: cardiac and renal abnormalities; intellectual disabilities and behavior problems; motor difficulties; speech, swallowing, and feeding difficulties.
Surveillance:
- MCAP syndrome: Follow up no less than every six months until age six years and at least yearly thereafter to monitor for neurosurgical complications, breathing or sleep disorders, seizures and orthopedic complications. Provisionally recommended imaging in early childhood includes brain MRI every six months for the first two years, then yearly until age eight years for neurologic complications (e.g., hydrocephalus, cerebellar tonsillar ectopia). Consider screening for Wilms tumor following the protocol suggested for Beckwith-Wiedemann syndrome (BWS) (by ultrasound examination every 3 months until age 8 years); however, tumor risk in PIK3CA-related segmental overgrowth is undetermined and appears to be lower than in BWS.
- CLOVES syndrome and FH: Monitoring for severe scoliosis, infiltrative lipomatous overgrowth, paraspinal high-flow lesions with spinal cord ischemia, lymphatic malformations, cutaneous vesicles, orthopedic problems, central phlebectasias, and thromboembolism.
Genetic counseling.
PIK3CA-associated segmental overgrowth is not typically inherited. Most affected individuals with MCAP reported to date (21/24) had somatic mosaicism for pathogenic variants in PIK3CA, suggesting that mutation occurred post-fertilization in one cell of the multicellular embryo. Two of 24 affected individuals had a de novo germline pathogenic variant in PIK3CA. All reported individuals with CLOVES and FH had somatic mosaicism for pathogenic variants in PIK3CA. No confirmed instances of vertical transmission or sib recurrence have been reported. Because family members are not known to have an increased risk, prenatal diagnosis is usually not indicated for family members.
Diagnosis
PIK3CA-associated segmental overgrowth includes brain (e.g., megalencephaly-capillary [MCAP] malformation syndrome, hemimegalencephaly) and segmental body overgrowth (e.g., CLOVES syndrome, fibroadipose hyperplasia [FH]) caused by heterozygous (usually somatic mosaic) PIK3CA pathogenic variants.
Suggestive Findings
PIK3CA-associated segmental overgrowth is suspected in an individual with clinical features of the following syndromes. Of note, some individuals with low-level mosaicism for PIK3CA somatic pathogenic variants may have phenotypes that do not meet clinical diagnostic criteria.
Megalencephaly-capillary malformation (MCAP) syndrome (Table 1) (Figure 1 and Figure 2) is characterized by the major findings (1) megalencephaly (MEG) (Figure 3) or hemimegalencephaly (HMEG) associated with abnormalities of muscle tone, seizures, and mild to severe intellectual disability, and (2) cutaneous capillary malformations with focal or generalized somatic overgrowth. Additional findings can include digital anomalies consisting of syndactyly and polydactyly; cortical malformations, most distinctively polymicrogyria (PMG) (Figure 3); and variable connective tissue dysplasia [Franceschini et al 2000, Robertson et al 2000, Giuliano et al 2004, Lapunzina et al 2004, Wright et al 2009, Martínez-Glez et al 2010, Mirzaa et al 2012].
syndrome.">Figure 1.
Features of MCAP syndrome. Photographs of an individual with MCAP syndrome demonstrating the apparent macrocephaly with prominent forehead (D); extensive capillary malformations (A-F1); bilateral 2-3-4 toe syndactyly (G,H); 3-4 finger syndactyly (F1,F2); (more...)
syndrome.">Figure 2.
Features of MCAP syndrome. A boy age 40 months with MCAP syndrome (left) and his unaffected twin sister (right). Note left-sided hemihypertrophy, typical facial features, bilateral 2-3 toe syndactyly, and connective tissue dysplasia with loose redundant (more...)
syndrome in three individuals (A-D, E-H, and I-L).">Figure 3.
Characteristic brain MRI of MCAP syndrome in three individuals (A-D, E-H, and I-L). Note: Megalencephaly with a prominent forehead (A, E, I); cerebellar tonsillar ectopia with a large cerebellum and crowded posterior fossa (A, E, I); ventriculomegaly (more...)
Hemimegalencephaly (HMEG) is characterized by partial or complete enlargement and dysplasia of a cerebral hemisphere, often with variable contralateral involvement. Complex abnormalities (typically noted on brain imaging) include cortical dysgenesis, abnormally increased white matter, and dilated and dysmorphic lateral ventricles [Barkovich & Chuang 1990, Flores-Sarnat 2002, Flores-Sarnat et al 2003].
Table 1.
Findings in MCAP Syndrome
| Finding | |||
|---|---|---|---|
| Major | Supportive | Secondary | |
| Early segmental overgrowth (brain > somatic tissues) | Progressive MEG or HMEG 1 |
|
|
| Developmental vascular disorders (abnormal vasculogenesis) | Cutaneous capillary malformations: 1
|
| |
| Digital anomalies | Syndactyly (2-3, 3-4, 2-3-4):
|
| |
| Cortical brain malformations | PMG |
| |
| Connective tissue dysplasia |
|
| |
DD = developmental delay; HMEG = hemimegalencephaly; MEG = megalencephaly; PMG = polymicrogyria
Based on Franceschini et al [2000], Robertson et al [2000], Giuliano et al [2004], Lapunzina et al [2004], Wright et al [2009], Martínez-Glez et al [2010]
- 1.
MCAP syndrome can be diagnosed based on clinical findings in individuals with classic features of MEG or HMEG (major finding 1) and characteristic capillary malformations (major finding 2).
CLOVES (or CLOVE) syndrome and fibroadipose hyperplasia (Table 2) may be associated with MEG or HMEG, and thus overlap with MCAP syndrome [Gucev et al 2008]. Findings include patchy segmental overgrowth associated with skeletal anomalies, lipomatosis, vascular malformations, and epidermal nevi. Given the clinical and molecular genetic overlap between CLOVES syndrome and fibroadipose hyperplasia, these two conditions may constitute a single large spectrum of somatic overgrowth.
CLOVES syndrome is characterized by congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies. CLOVES syndrome differs from MCAP syndrome by more striking growth dysregulation with complex congenital overgrowth of lipomatous tissues (typically manifest as a truncal lipomatous mass) and combined lymphatic and vascular malformations (Figure 4A). Skeletal anomalies include scoliosis, wide hands and feet, macrodactyly (Figure 4B), and prominent sandal-gap toes [Sapp et al 2007, Alomari 2009a].
Figure 4.
Features of CLOVES syndrome in a child with (A) a large lipomatous truncal mass that extends into the surrounding tissues and an overlying capillary malformation and (B) macrodactyly of the left foot
Fibroadipose hyperplasia, a severe overgrowth syndrome recently described in ten individuals with mosaic PIK3CA pathogenic variants [Lindhurst et al 2012], is characterized by progressive segmental overgrowth of visceral, subcutaneous, muscular, fibroadipose, and skeletal tissues, and may involve the trunk or extremities. Other variable features include lipomatous infiltration of muscle, progressive adipose dysregulation and regional lipohypoplasia, vascular malformations, testicular abnormalities, and polydactyly.
Table 2.
Classic Features of CLOVES Syndrome and Fibroadipose Hyperplasia
| Feature | CLOVES Syndrome | Fibroadipose Hyperplasia 1 |
|---|---|---|
| Overgrowth |
|
|
| Cutaneous & vascular malformations |
|
|
| Musculoskeletal/ acral abnormalities |
|
|
| Visceral abnormalities |
|
|
| Neurologic abnormalities |
| |
| Other |
|
- 1.
Features variably identified in ten affected individuals
Establishing the Diagnosis
PIK3CA-associated segmental overgrowth is confirmed in an individual with a pathogenic variant on one PIK3CA allele who meets clinical criteria. In an individual with ambiguous or mild clinical findings [Kurek et al 2012, Lindhurst et al 2012, Rivière et al 2012] (Table 3), identification of a PIK3CA pathogenic variant establishes the diagnosis of PIK3CA-associated segmental overgrowth.
Because the vast majority of reported PIK3CA pathogenic variants are postzygotic (and thus mosaic), more than one tissue may need to be tested.
- Experience suggests that sequence analysis of DNA derived from saliva or skin (whether visibly affected or not) has a higher detection rate than of peripheral blood-derived DNA.
- In highly focal disorders such as HMEG, CLOVES, and fibroadipose hyperplasia, pathogenic variants are only detectable in affected tissues. Therefore, absence of a pathogenic variant in a DNA sample is insufficient to exclude the diagnosis [Kurek et al 2012, Lee et al 2012, Lindhurst et al 2012].
- Failure to detect a PIK3CA pathogenic variant does not exclude a clinical diagnosis of PIK3CA-associated segmental overgrowth disorders in individuals with suggestive features, given that low-level mosaicism is observed in many individuals. Furthermore, locus heterogeneity is a possibility (see Differential Diagnosis).
- Sensitivity to detect low-level mosaicism of a PIK3CA pathogenic variant is theoretically greatest using massively parallel sequencing (also known as next-generation sequencing) in tissues other than blood, and in particular will be of high yield when analyzing affected tissues in disorders other than MCAP syndrome.
Table 3.
Molecular Genetic Testing Used in PIK3CA-associated Segmental Overgrowth
| Gene 1 | Method | Variants Detected 2 | Pathogenic Variant Detection Frequency by Method 3 |
|---|---|---|---|
| PIK3CA | Sequence analysis 4 | Sequence variants 5 | Dependent on phenotype, tissue analyzed, and method 6, 7, 8 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants.
- 3.
The ability of the test method used to detect a variant that is present in the indicated gene
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Most identified PIK3CA pathogenic variants to date are missense, with only a single in-frame 3-bp deletion identified in MCAP syndrome [Rivière et al 2012]. No nonsense or splice site variants, large deletions, or duplications involving PIK3CA have been identified to date.
- 6.
For MCAP syndrome: 21/24 individuals had somatic mosaicism for a PIK3CA pathogenic variant; 2/24 had a de novo PIK3CA germline variant; and 1/24 had inconclusive results with only one sample available for testing [Rivière et al 2012]. The level of mosaicism varied by the tissue being tested and ranged from 1% to 48%. In individuals in whom three or more tissues were analyzed, blood was the tissue in which the lowest level of mosaicism was observed [Rivière et al 2012]. The level of mosaicism was below 25% in 15 of 18 (83%) samples of blood-derived DNA and in 11 of 22 (45%) samples of saliva- or skin-derived DNA. Detection of these pathogenic variants was facilitated by massively parallel sequencing and would likely have been missed by standard Sanger sequence analysis.
- 7.
For CLOVES, FH, HMEG: Pathogenic variants were identified in affected tissues (including brain in hemimegalencephaly) with mutated allele frequencies ranging from 1% to 49% overall. The pathogenic variants were not identified in DNA derived from blood (or, in some studies, from either blood or saliva) [Kurek et al 2012, Lee et al 2012, Lindhurst et al 2012].
- 8.
For HMEG: The same PIK3CA pathogenic variant (c.1633G>A) was identified in four brain samples of affected individuals.
Clinical Characteristics
Differential Diagnosis
A number of overgrowth and megalencephaly disorders overlap with the PIK3CA-associated segmental overgrowth syndromes, including the following.
Hemimegalencephaly (HMEG) is characterized by enlargement and dysplasia of all or part of a cerebral hemisphere. In addition to CLOVES syndrome (discussed in this GeneReview), it can be isolated but has also been reported in association with disorders of focal somatic overgrowth and/or vascular malformations such as Klippel Trenauany syndrome, hypomelanosis of Ito, Proteus syndrome, linear nevus sebaceous syndrome, tuberous sclerosis complex, and nevoid basal cell carcinoma [Abdelhalim et al 2003, Sharma et al 2009, Pavlidis et al 2012]. Besides PIK3CA, mosaic pathogenic variants in other genes of the PI3K-AKT pathway (see Molecular Pathogenesis), including AKT3 and MTOR, have been identified in brain tissue from individuals with HMEG [Lee et al 2012, Poduri et al 2012].
Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome was first described in 2004 and has since been reported in 29 individuals [Mirzaa et al 2004, Colombani et al 2006, Garavelli et al 2007, Tohyama et al 2007, Pisano et al 2008, Tore et al 2009, Osterling et al 2011, Kariminejad et al 2013]. This disorder is characterized by significant, and most often congenital, megalencephaly (MEG), bilateral perisylvian polymicrogyria (PMG), postaxial polydactyly, and an increased risk for hydrocephalus. While its four core features, and primarily the neuroimaging manifestations, overlap with MCAP syndrome [Gripp et al 2009], MPPH syndrome can be primarily distinguished by the absence of vascular malformations, focal somatic overgrowth, and connective tissue dysplasia [Verkerk et al 2010]. De novo germline pathogenic variants in PIK3R2 and AKT3, two other core components of the PI3K-AKT pathway, have been identified in MPPH syndrome [Rivière et al 2012].
Klippel-Trenaunay syndrome (KTS) is characterized by disproportionate growth disturbance combined with cutaneous capillary, lymphatic, and venous malformations. KTS typically involves the lower extremities but may affect the upper extremities and may be bilateral. The findings are typically focal and usually spare the craniofacial region, distinguishing it from the more generalized overgrowth observed in PI3KCA-related segmental overgrowth syndromes [Oduber et al 2011].
Bannayan-Riley-Ruvalcaba syndrome (BRRS), the most severe end of the PTEN-related overgrowth spectrum, is characterized by macrocephaly, developmental delay, lipomatosis, intestinal hamartomatous polyposis, and pigmented macules of the penis. While capillary malformations have been seen in BRRS, they are typically isolated and not similar to the capillary malformations in MCAP syndrome. Furthermore, BRRS lacks the significant overgrowth (particularly the truncal lipomatous overgrowth), acral deformities, and other characteristic features of CLOVES syndrome and fibroadipose hyperplasia. BRRS is caused by germline pathogenic variants in PTEN. Most individuals with BRRS have normal intelligence.
Proteus syndrome, a severe overgrowth syndrome, is associated with disproportionate and asymmetric postnatal somatic overgrowth including skeletal overgrowth, cerebriform connective tissue nevi (CCTN), epidermal nevi, dysregulated adipose tissue, and vascular malformations. Proteus syndrome can be primarily distinguished from CLOVES syndrome and fibroadipose hyperplasia by the postnatal onset of overgrowth. Furthermore, Proteus syndrome lacks the characteristic truncal fatty-vascular mass, spinal paraspinal fast-flow lesions and the acral abnormalities characteristic of CLOVES syndrome [Biesecker et al 1999]. Severely deforming and progressive skeletal overgrowth and poor prognosis occur in both disorders. Mosaic pathogenic variants in AKT1 were identified in affected tissues of individuals with Proteus syndrome [Lindhurst et al 2011].
Hemihyperplasia-multiple lipomatosis (HHML) syndrome, a distinct milder form of overgrowth, is characterized by moderate somatic asymmetry and overgrowth with subcutaneous lipomas and occasional vascular malformations, but lacks deep vascular malformations, epidermal nevi, cerebriform connective tissue nevi (CCTN), and hyperostosis. HHML syndrome may overlap with CLOVES syndrome given that overgrowth can be progressive and spinal complications and scoliosis have been reported [Lindhurst et al 2012].
SOLAMEN syndrome is characterized by atypical features of Cowden syndrome including segmental overgrowth, lipomatosis, arteriovenous malformation, and epidermal nevi. It is also associated with tumors such as ovarian cystadenoma, multiple breast tumors, and thyroid adenomas. Fibrocystic breast disease, gingival papules, and multinodular goiter have also been reported. SOLAMEN syndrome results from biallelic inactivation of PTEN (type 2 mosaicism), restricted to the atypical lesions [Caux et al 2007]. (See PTEN Hamartoma Tumor Syndrome.)
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual with PIK3CA-associated segmental overgrowth, the following evaluations are recommended:
- A thorough history to identify key features of PIK3CA-associated segmental overgrowth
- A physical examination including a thorough skin, cardiac, abdominal, and musculoskeletal evaluation, as well as a detailed neurologic assessment
- Investigations to detect abnormalities before they result in significant morbidity/mortality:
- Baseline brain and spinal cord imaging, especially in children with hemimegalencephaly (HMEG) and MCAP syndrome for early detection of cortical dysplasia, ventriculomegaly, and cerebellar tonsillar ectopia.
- A cardiovascular assessment including a baseline echocardiogram and electrocardiogram to evaluate for cardiovascular malformations and rhythm abnormalities
- A baseline renal ultrasound to evaluate for structural renal abnormalities
- Surgical and orthopedic referrals for individuals suspected of having CLOVES syndrome or fibroadipose hyperplasia, and individuals with MCAP syndrome with focal somatic overgrowth or leg-length discrepancy
Treatment of Manifestations
Patients with PIK3CA-associated segmental overgrowth benefit from a coordinated and multidisciplinary clinical approach tailored to the individual's specific needs and manifestations.
Referral to the appropriate specialist(s) is recommended for the following findings:
- Significant or lipomatous segmental overgrowth: referral to a surgeon and/or thoracic surgeon (when lipomatous overgrowth involves the trunk)
- Leg-length discrepancy secondary to segmental somatic overgrowth
- Cardiac abnormalities (i.e., structural cardiovascular disease and arrhythmias)
- Renal abnormalities
- Intellectual disability and/or difficulties with learning, behavior, or speech, or motor difficulties
- Speech, swallowing, and feeding difficulties
Neurologic and neurosurgical manifestations
- MCAP syndrome. Findings warranting neurosurgical referral include rapidly enlarging OFC, obstructive hydrocephalus, symptoms of raised intracranial pressure, and progressive or symptomatic cerebellar tonsillar ectopia (CBTE) or Chiari malformation. Early treatment of hydrocephalus may reduce the risk for progressive CBTE, but data are lacking to determine the most appropriate neurosurgical management. In recent years, favorable outcomes have been observed with ventriculostomy of the third ventricle (rather than insertion of a ventriculo-peritoneal shunt), suggesting that the neurosurgical management of hydrocephalus in MCAP syndrome is evolving.
- HMEG. Individuals are at risk for severe early-onset epilepsy, focal neurologic signs such as hemiparesis, and severe intellectual disability. Epilepsy and intellectual disability may be improved by hemispherectomy [Di Rocco et al 2006, Kwan et al 2008].
- Individuals with HMEG and MCAP syndrome with polymicrogyria (PMG) are at increased risk for epilepsy; thus, long-term neurologic follow up is warranted, and many require long-term antiepileptic treatment [Mirzaa et al 2012].
Somatic overgrowth, vascular, lymphatic and musculoskeletal manifestations. CLOVES syndrome and fibroadipose hyperplasia (FH) are associated with severe focal overgrowth, vascular malformations, and orthopedic complications with significant morbidities. Prompt diagnosis (by MR/CT and angiography) is warranted. Most individuals undergo (often several) debulking or orthopedic procedures with significant ensuing complications (see Surveillance).
The following are the main treatment considerations in CLOVES syndrome:
- The characteristic truncal lipomatous mass infiltrates surrounding tissues and often requires surgical excision. Severe scoliosis, large truncal mass, paraspinal high-flow lesions with spinal cord ischemia, lymphatic malformations, cutaneous vesicles, orthopedic problems of the feet and hands, and central phlebectasia/thromboembolism are examples of significant morbidities that need active or prophylactic medical intervention.
- Paraspinal and intraspinal extension have significant risk for compression of the cord, thecal sac, and nerve roots, with resultant major neurologic deficits, warranting prompt diagnosis and multidisciplinary care [Alomari 2009a].
- Given the risk for thromboembolism in CLOVES syndrome, appropriate prophylactic measures including anticoagulation and caval filtration, particularly in the perioperative period, are recommended. Central and thoracic phlebectasia in individuals with CLOVES syndrome should be considered an indication for placement of a superior vena cava (SVC) filter.
FH is associated with severe progressive overgrowth of fibrous and adipose tissues. While the severity and natural history varied among reported individuals, thorough surgical and orthopedic evaluations are warranted. Most individuals (8/10) underwent extensive debulking or orthopedic procedures.
Surveillance
MCAP syndrome. Provisional surveillance guidelines include regular follow up, no less than every six months until age six years, and at least yearly thereafter. At each visit, the following are recommended with appropriate testing for any positive finding:
- A medical history with attention to:
- Childhood cancer
- Breathing or sleep problems
- Seizures or other undefined spells, headaches, or new or worsening neurologic symptoms
- A detailed neurologic evaluation
- Brain MRI. Based on limited retrospective data available, the risk for hydrocephalus, cerebellar tonsillar ectopia, or both with low brain stem or high spinal cord compression, appears to be highest in the first two years. Brain MRI is provisionally recommended every six months from birth to age two years, and annually from age two to six years. In older individuals, the frequency should be based on prior results and clinical findings, with particular attention to apnea or other abnormal patterns of respiration, headaches, changes in gait, or other neurologic problems.
- Renal ultrasound. Until additional data are available, screening for Wilms tumor following guidelines developed for Beckwith-Wiedemann syndrome may be considered (i.e., renal ultrasound examination every 3 months until age 8 years).
CLOVES syndrome
- Given the associated morbidities including severe scoliosis, infiltrative lipomatous overgrowth, paraspinal high-flow lesions with spinal cord ischemia, lymphatic malformations, cutaneous vesicles, orthopedic problems, central phlebectasias and thromboembolism, individuals with CLOVES syndrome require surveillance tailored to their specific needs with particular attention to surgical care [Sapp et al 2007, Alomari 2011, Alomari et al 2011].
- Commonly occurring postoperative complications of surgical excision of the truncal lipomatous mass include recurrence, hypervascularity, and infiltrative growth. Therefore, diligent surgical care and monitoring are recommended.
Fibroadipose hyperplasia. Data regarding the natural history of fibroadipose hyperplasia are limited. However, given the extensive degree of somatic overgrowth in most individuals, the same surveillance guidelines for CLOVES are tentatively recommended for individuals with FH [Lindhurst et al 2012].
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.