- What are the differential diagnoses for 6-month old boy who was born with isolated hemihypertrophy of the left lower limb, and was found to have a pathogenic variant of the PIK3CAgene ina mosaic pattern(22%), and is CLOVES syndrome indeed the most suitable diagnosis forhis profile?
- What in for mationexists regarding the most probable diagnosis in terms of prognosis, quality oflife, possible complications and similar patients,and what is the necessary follow-up for the patient?
- What are the possible treatment options (surgical etc.) for treating the patient’s hemihypertrophy, and are there possible targeted treatment options forPIK3CAmutations which can be beneficial for the patient?
The patient is a 6 month-old boy who was born with hemihypertrophy of the left lower limb, which involves toes II-IV as well as the soft tissues of the plantar region. Genetic analysis (CeGaT) ofa skin biopsy fromthe leftfootrevealeda pathogenic variantin PIK3CAina mosaic pattern, which is deemedto cause the patient’shemihypertrophy.
Medical Meta Findings
Based on the most recent guidelines1 for the diagnosis and classification of the patient’s condition, his genetic and clinical pictures fit within a group of diagnoses termed PIK3CA-Related Over-growth Spectrum disorders (PROS).
PROS is a group which encompasses a spectrum of syndromes which can be quite different from one another, but also often have overlapping features. The exact diagnosis within the group can often be challenging to make, but it is also not necessarily clinically relevant. CLOVES syndrome, which was proposed as a diagnosis for this patient, is also part of the PROS disorders.
1a. According to the above guidelines, experts now propose to split PROS into two groups – these are not specific syndromes such as CLOVES or others in the PROS group, but rather sub-definitions which are important for outlining the correct management based on the features of each group:
MCAP (Megalencephaly-capillary malformation) PROS:
Activating, mosaic PIK3CA variant – which the patient has Megalencephaly (large brain, which the patient does not have based on current findings) and/or polymicrogyria (an abnormality of brain development which the patient also does not have based on current findings).
Extra-CNS overgrowth (overgrowth of a tissue or organ outside of the central nervous system. which the patient has) and/or vascular findings including cutaneous (skin) changes which the patient does not seem to have.
NON-MCAP PROS –
Activating, mosaic PIK3CA variant – which the patient has No significant Megalencephaly or polymicrogyria or Syrinx (a fluid filled cavity in the spinal cord) – the patient fits this criteria
Extra-CNS overgrowth and vascular or cutaneous findings – the patient has extra-CNS overgrowth but no currently known vascular or skin findings.
Based on the above criteria, the patient can likely be categorized as having non-MCAP PROS.
1b. In addition to these definitions, experts have also classified the PROS disorders depending on the phenotypic/clinical spectrum, depending on whether the clinical picture is localized/tissue specific, or whether it is multi-systemic with possible brain involvement.
The diagnoses which are most similar to the patient’s state are detailed below2:
*There are a variety of other disorders which we have not detailed in the below table due to their irrelevance to the patient’s current clinical picture.
Localized or tissue-specific
Multi-systemic and with possible brain involvement
Macrodactyly – Macrodactyly is a fibrofatty enlargement of a limb or part of a limb.
Fibroadipose Overgrowth / Hemihyperplasia-Multiple Lipomatosis (FAO/HHML):
FAO – FAO is characterized by segmental and progressive overgrowth of subcutaneous and visceral fibroadipose tissue. It may also be associated with skeletal and muscular overgrowth.
HHML – HHML is characterized by moderate abnormalities of asymmetry and overgrowth with multiple subcutaneous lipomata, and static or mildly progressive hemihyperplasia.
CLOVES (Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Scoliosis/Skeletal and Spinal Abnormalities syndrome):
CLOVES syndrome is characterized by congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis, and spinal abnormalities.
Lipomatous overgrowth often affects the front and back of the torso, as well as limbs, fingers, and toes
Bone abnormalities, including scoliosis and macrodactyly
Many people with CLOVES syndrome experience worsening symptoms over time Overlap with symptoms of hemihyperplasia-multiple lipomatosis and fibroadipose hyperplasia may also occur.
- Further tests and follow up, possible complications
It is important to note that the majority of patients with PROS experience a progressive disease course. First clinical manifestations are typically observed within the patient’s first year of life, with additional manifestations possibly becoming apparent later. When considering the specific diagnosis for these disorders, care should be taken to consider this possibility3.
Having said that, based on the current guidelines4 there are several other diagnostic and surveillance tests which can be undertaken to rule our further involvement and/or be used as follow up according to the physician’s discretion:
A range of developmental vascular anomalies comprise part of the diagnostic criteria of PROS. Vascular malformations are frequent in PROS, occurring in 59% of patients in one recent study.
MRI/A/V scans of the chest, abdomen, pelvis and extremities at the time of initial diagnosis depending on the
involvement of clinical findings (including tissue overgrowth and /or superficial vascular anomalies) and Doppler ultrasounds of affected limbs are recommended. Because these disorders may be associated with progression, the frequency of follow up should be based on clinical history and physical examination.
Individuals with PROS have an increased risk for deep venous thrombosis (DVT)/pulmonary embolism (PE), especially those with combined capillary-lymphatic-venous malformations (which the patient is not known to have as of now). Incidence has been reported to be 17% and 14–22% for DVT and PE, respectively (64% occurring
after surgery or sclerotherapy).
Pre-disposition to thrombosis is likely to be multifactorial with risk factors including chronic stasis within vascular malformations, stasis from impaired mobility (e.g., following surgery or dehydration), decreased anticoagulant proteins, and effects of the PIK3CA variant on vascular endothelium
Regular growth measurements as part of a routine neonatal/pediatric assessment are recommended in all individuals with PROS . Growth assessment should specifically seek asymmetry of the legs, and all individuals with leg length discrepancy (LLD) should be referred to an orthopedic surgeon for review and management. Of note, LLD may be either true or anatomical because of asymmetric overgrowth of the lower limbs, or functional because of involvement of the hips (by hip dysplasia or contractures).
If rapid growth of a specific body area is observed, referral should be made for consideration of other monitoring techniques such as volumetric studies. Imaging studies, including angiography should also be considered.
Risk of malignancies – Non-MCAP PROS disorders are associated with somatic mosaicism for PIK3CA pathogenic variants at the cancer-related mutational hotspots.
Anecdotal observations so far suggest a 1%–3.3% Wilms Tumor risk in cases with a confirmed genetic diagnosis. Recently the fourth individual with asymmetric overgrowth due to a somatic PIK3CA variant who had a Wilms
tumor or nephroblastomatosis (a pre-tumor growth). Similarly to two previously reported individuals with renal tumors, the somatic PIK3CA variant they had was in the commonly mutated codon 1047, which is the site of mutation the patient has. Codon 1047 is most commonly affected by somatic variants in PROS, and fibroadipose overgrowth is common in individuals with codon 1047.
There have been four case reports of individuals with PROS who developed other types of cancer including leukemia, vestibular schwannoma, retinoblastoma, and meningioma.
Otherwise, the most common benign tumors in PROS are lipomas which may be multiple and usually remain stable in size.
In a recent review5 of tumor risk assessment in PROS, experts concluded that it is likely that the overall risk of Wilms Tumor and other malignant/pre-malignant renal findings actually falls below 1% , indicating that screening is not warranted. These experts, as well as the current guidelines, concluded that tumor screening should be performed
at the discretion of the treating physician based on the genetic change and clinical features of the PROS presentation, as well as the family perspective.
Recently, an interesting study6 proposed an additional method of screening for risk of tumor in patients with PROS. The researchers found high levels of PIK3CA variant in urine cell-free DNA (cfDNA) that correlated with a history of nephroblastomatosis or Wilms tumor compared with individuals without known renal involvement.
In individuals with non-MCAP PROS, segmental overgrowth may be extreme, with concomitant paucity of adipose tissue in non- overgrown areas.
Liposuction has been used to debulk fat overgrowth rather than open resection, however only subjective assessment of outcomes have been made, and there is a possible risk of post-operative weeping of lymphatic fluid7.
Surgical debulking is an option for localized overgrowth but the efficacy of surgical debulking is not proven, as there are outstanding questions about the possibility and speed of regrowth following surgery.
This article8 presents an algorithm and surgical techniques for dealing with children with macrodactyly in such a way that should make a complex problem more easily approachable for treating physicians.
The below targeted therapy options all target the mTOR/PIK3CA/AKT pathway and are being investigated for the treatment of PROS.
FDA-approved for other indications – yes (kidney transplant receivers and other uses)
Efficacy evidence: A study9 which was published in 2019 evaluated the efficacy of low-dose Sirolimus in 39 adults and children with PROS and progressive overgrowth (mean age 16.6, range 3-48).
In the 30 patients who were evaluable after 26 weeks of treatment,
In addition, there was a trend toward
greater tissue volume reduction in participants with predominant adipose overgrowth than in participants without predominant adipose overgrowth. There were no apparent differences with respect to age, genotype, or the presence/absence of vascular/venous malformations, though it is hard to make these kind of conclusions based on such a small patient population.
Side effects: In the above study, 72% of patients had at least one side effect of the treatment. In 37% these were severe
adverse events, causing withdrawal from the study by 18% of patients. The most common type of adverse event was infection (41% of participants), followed by blood or lymphatic disorders (21%). Clinically
important adverse events included grade 4 neutropenia, interstitial pneumonitis (lung inflammation and scarring), and sirolimus hypersensitivity syndrome.
How to get it?: Sirolimus is included in the Israeli Health Basket10 for other indications. It has been proposed to the patient by his treating physicians at Schneider Hospital and approval from the ministry of health is currently underway. Experts’ opinions:
Dr. Martinez Lopez: Regarding treatment, an mTOR inhibitor would be adequate at the presenttime in order to stop overgrowth and the developmentof other manifestations
Dr. Canaud: If you don’t see any vascular malformations within the leg (and particularly lymphatic malformations), sirolimus will have no impacton the overgrowth. Sirolimus is associated with adverse events and only improving lymphatic malformations. It improves inflammatory flares and excessive swelling that I don’t see here.
FDA-approved for other indications – yes (certain types of cancer)
A study11 which was published in 2018 evaluated the efficacy of Alpelisib for the treatment of PROS in several ways. The researchers first designed a mouse model of PROS/CLOVES that partially resembles the human disease, and demonstrated the efficacy of Alpelisib in preventing and improving organ dysfunction.
The researchers also showed in preclinical studies that Alpelisib was more effective than Sirolimus in blocking the PIK3CA pathway and reducing tumor growth in mice.
On the basis of these results, Alpelisib was used to treat 19 patients with PROS. Children received Alpelisib at a dose of 50 mg/day.
12 of the patients had had previous debulking surgeries, and 8 had been previously treated with Sirolimus with no significant improvement.
Out of the patients treated12, 5 patients had the same mutation as our patient. Out of these 5, 3 patients had presentations very similar to the patient’s, with isolated hemihypertrophy of the lower foot/limb as the only current feature, at ages 4, 19 and 32. These 3 patients also had very similar percentage of mutation mosaicism, ranging from 14-25%.
The drug improved the disease symptoms in all patients. In patients with hemihypertrophy, reduction in size was
seen both by clinical measurements and by radiographical measurements. In other patients with vascular tumors, scoliosis or other features, improvement was seen across all parameters.
In the 3 patients above who are similar to our patient in mutation, mosaicism % and presentation, reduction of size
was seen as follows:
*4 y/o patient: After 3 months -10% clinically and -28% radiographically. After 6 months -16.7% clinically and -49% radiographically.
*19 y/o patient: After 3 months -11.9% clinically and -17.2% radiographically. After 6 months -14.8% clinically and
*32 y/o patient: After 3 months -8.6% clinically and -30.2% radiographically. After 6 months -13.8% clinically and
-37.2% radiographically. Mean values of limb circumference reduction after 3 months and 6 months of treatment, respectively : clinically -10%, -15%, radiographically -25%, -38%.
In addition, all 3 patients reported improvement in tiredness as well as improvement of the walking distance.
Side effects: No significant side effects were reported, apart from temporary discrete mouth ulcers in 3 patients which resolved spontaneously. No patients discontinued treatment.
How to get it?: Alpelisib is included in the Israeli Health basket for other indications. There is a currently recruiting phase II clinical trial evaluating its efficacy which is recruiting patients over the age of 2. Novartis, the manufacturer, also has an expanded access program for patients with PROS which is designated for patients over the age of 2 as well.
However, we have reached out to Novartis to see if the age requirement can be waived for our patient.
Dr. Canaud: You will have to consider in the near future (notnow because your patient is too young), Alpelisib, which is currently undergoing clinical trials (NCT04285723, NCT04589650). We identified this drug a few years ago and we have #100 patients treated at Necker. We confirmed the efficacy and the good safety profile. Results of EPIK P1 will be released soon (NCT04285723).
Dr. Semple: Perhaps the mostpromising experimental treatmentavailable is Alpelisib from Novartis, which under certain circumstances can be accessed either via the current trial, or on a compassionate basis as partof the managed access program.
Dr. Lopez Gutierrez: I would recommend to initiate compassionate use of Alpelisib , an specific PIK3CA inhibitor. We currently have more than 40 patients under treatmentand conducting a major clinical trial with promising results.
FDA-approved for other indications – no (is currently in phase II clinical trials for PROS / Proteus Syndrome) Efficacy evidence:
Miransertib, an oral inhibitor of AKT, demonstrated antiproliferative activity in primary fibroblasts derived from patients (N = 6) with PIK3CA-related disorders13.
In preliminary results of a phase 1/2 study of miransertib in 15 patients with PROS and Proteus Syndrome,
A case series15 with miransertib in two children with severe PROS reported an objective clinical response in a patient with CLOVES and reduced seizure frequency and improved quality of life in a patient with FIL and HMEG; no significant adverse events were reported.
Side effects: No significant side effects have been reported to date.
How to get it?: The phase 1/2 study16 whose results are reported above is still active but no longer recruiting. The expanded access program for the drug also seems to be inactive at the moment. The manufacturer of the drug is Merck, if need be they can be contacted them in the future to check for additional programs and trials.
Experts we contacted and received replies from by email are presented below.
*Any further correspondence with the experts presented below will be forwarded to the patient.
Description and contact
Prof. Canaud17 is a pediatric nephrologist at Necker Children’s Hospital in Paris with special interest in genetic diseases, including PROS. His team were the ones to pioneer the discovery of Alpelisib as a treatment for CLOVES in 2018, and he is currently leading the clinical trials of Alpelisib at the Paris site. He has also written several articles on the diagnosis and management of PROS.
I agree that the clinical presentation is due to the PIK3CA variant that you have identified. Certainly, surgery will be at some point necessary but I would recommend to wait up to the baby starts to stand up and walk. Surgical procedures usually improve transiently patient but then the overgrowth can recur becoming more anarchic and more difficult to treat.
If you don’t see any vascular malformations within the leg (and particularly lymphatic malformations), sirolimus/rapamycin will have no impact on the overgrowth. Sirolimus is associated with adverse events and only improving lymphatic malformations. Sirolimus improves inflammatory flares and excessive swelling that I don’t see here.
You will have to consider in a near future (not now because your patient is too young), alpelisib (PIK3CA inhibitor) that is currently undergoing clinical trial (NCT04285723, NCT04589650). We identified this drug few years ago and we have #100 patients treated at Necker. We confirm the efficacy and the good safety profile. Results of EPIK P1 will be released soon (NCT04285723).
Regarding the use of Alpelisib at a younger age he responded – I would wait up to the age of 2 years before starting (50mg per day) Regarding recommended follow-up – Usually we monitor the target lesion (i.e. the foot here) with MRI before and then every 6 months on treatment. We recommend to monitor the kidneys every year by US up to age of 6 years because of extremely low risk of Wilms tumor (that I never saw)
Regarding risk of malignancy – No particular risk of malignancy in this population (except perhaps Wilms tumor). Risk of diabetes (mostly in adults) after alpelisib introduction
Leslie G. Biesecker, M.D.
Dr. Biesecker is a clinical and molecular geneticist and is the chief of the Center for Precision Health Research at the National Human Genome Research Institute (NHGRI) of the National Institutes of Health. He uses genetic and genomic technologies to study the etiology of inherited disorders. He has a special research interest in genetic diseases which involve the PIK3CA/AKT pathway and has led and published several clinical studies on PROS. Email: email@example.com
Dr. Biesecker replied that If the family would like to contact them, they are welcome to do so directly.
Description and contact
Sofia Douzgou M.D., Ph.D
Dr. Douzgou is a medical geneticist, Senior Consultant in the Department of Medical Genetics in Haukeland University Hospital, Norway and at the Manchester Centre for Genomic Medicine, United Kingdom. She was part of the team of experts who wrote the most recent guidelines for PROS. Email: firstname.lastname@example.org
Thank you for sending over details of this patient although it is unclear whether they are under your care or whether you are seeing them as part of a Research protocol they consented to.
I do not provide remote opinions about patients I have not seen/examined. However, I see that the patient has been seen by a medical geneticist who is welcome to contact me with any further questions.
From the information you provide in your email, I see that a multi- systemic diagnosis is proposed in a patient with localized (although extended localized) presentation. Maybe this is to allow for possible age (or time)-dependent symptoms.
Regarding treatment, I think the medical geneticist who is seeing them could have a look on whether the patient is eligible for any of the clinicaltrials for example :
Managed Access Program (MAP) to Provide Access to Alpelisib (BYL719)
Robert Semple, M.D., Ph.D.
Prof. Semple is the Chair of Translational Molecular Medicine at the University of Edinburgh and has a particular interest in finding treatment for patients with PROS and was part of the team of experts who wrote the most recent guidelines for PROS. Email: email@example.com
There is no doubt that this child has PIK3CA-related overgrowth. CLOVES is one part of a wide spectrum, and whether or not CLOVES is precisely the correct description is somewhat academic. Perhaps the best I can do to help is to share the attached document in which a panel of international experts, including me, summarized current thinking about treatment and diagnosis, recognizing that must of current recommendation is based on case series only.
Perhaps the most promising experimental treatment available is Alpelisib from Novartis, which under certain circumstances can be accessed either via the current trial, or on a compassionate basis as part of the managed access program.
JC Lopez Gutierrez, MD
Dr. López Gutiérrez specializes in Pediatric Surgery and Pediatric Reconstructive Surgery. As well as being Head of Department at Madrid University Hospital, he is also Head of the Congenital Vascular Defects Unit at La Paz Hospital (Madrid). He has published several articles on the topic of PROS and currently leads the clinical trial of Alpelisib in Madrid.
In my opinion the patient physical examination does not fit with CLOVES syndrome has there is no evidence of lipomas, epidermal nevus , vascular anomaly or scoliosis. The boy suffer from an aggressive form foot macrodactyly in the context of PROS
.Orthopedic surgical correction is mandatory. In addition and considering the unusual aggressivity in this patient I would recommend to initiate compassionate use of Alpelisib , an specific PIK3CA inhibitor. We currently have more than 40 patients under treatment and conducting a major clinical trial with promising results.