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ARTICLE
Alpelisib for the treatment of PIK3CA-related head
and neck lymphatic malformations and overgrowth
Tara L. Wenger
1,2,
*, Sheila Ganti
2,3
, Catherine Bull
2,3
, Erika Lutsky
3
, James T. Bennett
1,4
,
Kaitlyn Zenner
5
, Dana M. Jensen
4
, Victoria Dmyterko
4
, Ezgi Mercan
6
, Giri M. Shivaram
2,7
,
Seth D. Friedman
2
, Michael Bindschadler
8
, Madeleine Drusin
3,5
, Jonathan N. Perkins
3,5
,
Ada Kong
9
, Randall A. Bly
2,3,5
, John P. Dahl
2,3,5
, Juliana Bonilla-Velez
2,3,5
,
Jonathan A. Perkins
2,3,5
ARTICLE INFO
Article history:
Received 12 May 2022
Received in revised form
26 July 2022
Accepted 27 July 2022
Available online 6 September 2022
Keywords:
Alpelisib
Infiltrating lipomatosis
Lymphatic malformation
PIK3CA-related overgrowth
spectrum (PROS)
Precision medicine
ABSTRACT
Purpose: PIK3CA-related overgrowth spectrum (PROS) conditions of the head and neck are
treatment challenges. Traditionally, these conditions require multiple invasive interventions,
with incomplete malformation removal, disfigurement, and possible dysfunction. Use of the
PI3K inhibitor alpelisib, previously shown to be effective in PROS, has not been reported in
PIK3CA-associated head and neck lymphatic malformations (HNLMs) or facial infiltrating
lipomatosis (FIL). We describe prospective treatment of 5 children with PIK3CA-associated
HNLMs or head and neck FIL with alpelisib monotherapy.
Methods: A total of 5 children with PIK3CA-associated HNLMs (n=4) or FIL (n=1) received
alpelisib monotherapy (aged 2-12 years). Treatment response was determined by parental report,
clinical evaluation, diary/questionnaire, and standardized clinical photography, measuring facial
volume through 3-dimensional photos and magnetic resonance imaging.
Results: All participants had reduction in the size of lesion, and all had improvement or reso-
lution of malformation inflammation/pain/bleeding. Common invasive therapy was avoided (ie,
tracheotomy). After 6 or more months of alpelisib therapy, facial volume was reduced (range
1%-20%) and magnetic resonance imaging anomaly volume (range 0%-23%) were reduced, and
there was improvement in swallowing, upper airway patency, and speech clarity.
Conclusion: Individuals with head and neck PROS treated with alpelisib had decreased malformation
size and locoregional overgrowth, improved function and symptoms, and fewer invasive procedures.
©2022 American College of Medical Genetics and Genomics.
Published by Elsevier Inc. All rights reserved.
Introduction
Mosaic activating variants in PIK3CA are found in several
distinct life-threatening and disfiguring head and neck condi-
tions, including isolated head and neck lymphatic
malformations (HNLMs) and PIK3CA-related overgrowth
spectrum (PROS).
1-3
Approximately two-thirds of all isolated
lymphatic malformations occur in the head and neck, whereas,
involvement of the head and neck is variable in PROS, with
decreasing relative frequency in facial infiltrating lipomatosis
*
Correspondence and requests for materials should be addressed to Tara L. Wenger, Seattle Children's Hospital, 4800 Sand Point Way NE, Mail Stop
OA.9.220, Seattle, WA 98105. E-mail address: Tara.Wenger@seattlechildrens.org
Affiliations are at the end of the document.
Genetics in Medicine (2022) 24, 2318–2328
www.journals.elsevier.com/genetics-in-medicine
doi: https://doi.org/10.1016/j.gim.2022.07.026
1098-3600/©2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
(FIL); megalencephaly-capillary malformation syndrome;
Klippel-Trenaunay-Weber syndrome (KTS); and congenital
lipomatous overgrowth, vascular malformations, epidermal
nevi, scoliosis, and spinal syndrome (CLOVES).
4-11
Head and neck involvement of PIK3CA-related condi-
tions is uniquely problematic because normal function of
many structures is compromised. Upper airway compression
from overgrown soft and bony tissue distort and narrow the
airway lumen causing intermittent or constant respiratory
distress, obstructive sleep apnea, or death. Sudden HNLM
swelling from inflammation can place affected infants at risk
for acute airway compromise. Macroglossia from tissue
overgrowth impairs tongue mobility, causing sleep apnea,
swallowing dysfunction, and difficulty in speech produc-
tion. HNLM involving oral and pharyngeal mucosa causes
chronic pain and bleeding. Orbital involvement, although
uncommon, can affect vision and induce episodic painful
proptosis. Ear involvement causes auricular overgrowth,
lymphatic otorrhea, and conductive hearing loss from ear
canal occlusion. Overgrowth of the craniofacial skeleton and
abnormal tooth development are frequently present in
HNLM and head and neck PROS, causing severe dental and
skeletal malocclusion, with facial skeletal disfigurement.
Invasive interventions focused on tissue ablation and func-
tional improvement have been the mainstay of treatment.
Unfortunately, invasive interventions in extensive bilateral
HNLM are not sufficient for removal of all the affected
tissue and can cause disfigurement and persistent functional
compromise. Consequently, many patients with bilateral
HNLM require long-term gastrostomy and tracheostomy
tubes. Complete removal or ablation of affected tissue is
challenging and even impossible because of proximity to
blood vessels, nerves, and other critical structures. For these
reasons, careful consideration of the type of treatment
applied to HNLM and PROS head and neck conditions is
necessary.
12
Mosaic gain-of-function postzygotic somatic gene vari-
ants in PIK3CA underlie most HNLM and head and neck
PROS, allowing targeted medical therapy. Large reviews of
genotype–phenotype correlation in PIK3CA-related diseases
typically distinguish between involvement of central ner-
vous system vs involvement of extra–central nervous system
and major diagnostic category but do not specifically iden-
tify individuals whose PROS includes the head and neck.
2
Mussa et al
13
identified that 70% of individuals with
PIK3CA-related diseases have 1 of 10 pathogenic variants,
with the remaining 30% have 81 other variants. The most
common variants in lymphatic malformations are
p.His1047Arg, p.Glu542Lys, and p.Glu545Lys.
3
Previ-
ously, empirical use of the mTOR inhibitor, sirolimus
(Rapamune), a downstream inhibitor of the PI3K pathway,
was used to treat a variety of lymphatic conditions,
including postoperative lymphorrhea. Reduction of malfor-
mation size in a heterogeneous group of HNLM with un-
known genotype was inconsistent and not objectively
measured.
14-20
This inconsistent response was also present
when sirolimus was used for PROS conditions, especially
FIL. Sirolimus has significant side effects, unknown optimal
dosing, and is an immunosuppressant causing some children
to discontinue therapy.
21,22
Many children with large
HNLM already have some degree of immunosuppression,
therefore, immunosuppressant use is not trivial.
23
Alpelisib is an upstream PI3K inhibitor and is effective
for treatment of breast cancers with pathogenic PIK3CA
variants.
24-28
It was approved in May 2019 by the US Food
and Drug Administration (FDA) for breast cancer, although,
it was already in use internationally. It is well tolerated, with
the major side effects in alpelisib-treated patients with breast
cancer being rash
29
and hyperglycemia.
30,31
Before its FDA approval, in France and Spain, alpelisib
was also used to treat patients with noncancerous PIK3CA-
related overgrowth, most of whom had CLOVES pheno-
type.
32,33
Since then, 1 additional patient with CLOVES
phenotype also showed clinical improvement.
34
Each re-
ported patient had severe life-threatening disease and/or was
scheduled to undergo debulking surgery when therapy was
initiated. All reported patients had reduction in the size of
the affected regions and dramatic clinical improvements. Of
the 21 reported patients, only 2 had PROS affecting the head
and neck, and both had a decrease in facial tumor bulk after
alpelisib treatment. One patient had improved eye opening.
There are no reports about treatment of non-PROS HNLM
and related conditions with alpelisib. Data from the EPIK-
P1 (NCT04285723) trial compared symptoms and radio-
logic response to alpelisib in 37 patients with PIK3CA-
related overgrowth. Among these patients, 27% had a
radiologic response of >20% reduction in volume compared
with baseline by week 24 of therapy. The most common
side effects reported were diarrhea (16%), stomatitis (16%),
and hyperglycemia (12%). On the basis of this trial data, the
FDA approved alpelisib for the treatment of PIK3CA-related
overgrowth in individuals aged older than 2 years with se-
vere disease on April 5, 2022.
This report describes the effect of prospective alpelisib
monotherapy in 5 children with PIK3CA-associated HNLMs
(n=4) and FIL (n=1).
Materials and Methods
All patients received care through the Vascular Anomalies
Center at Seattle Children’s Hospital. Expanded use autho-
rization was obtained from the Food and Drug Administration
and Novartis Pharmaceuticals for the use of alpelisib. Eligi-
bility criteria included patient age of at least 2 years and
documentation of a pathogenic or likely pathogenic variant in
PIK3CA. Detection of PIK3CA variants in malformation
tissue was obtained using a high-depth, 44-gene, targeted
next-generation sequencing panel, referred to as Vascular
Anomalies sequencing panel (VANseq).
35,36
Cell-free DNA
was isolated from malformation cyst fluid, and pathogenic
variants were detected using digital droplet polymerase chain
T.L. Wenger et al. 2319
reaction (ddPCR) as previously reported.
37
Variant allele
fractions (VAF%) are reported for all samples in Table 1. All
individuals underwent review of treatment indications by
Novartis’program officers. Families were enrolled in Seattle
Children’s Hospital Institutional Review Board approved
STUDY00002044 after consent. All individuals were
screened for eligibility through clinical examination and
laboratory evaluation and excluded for hyperglycemia.
Baseline contrast head and neck magnetic resonance imaging
(MRI) and clinical 3-dimensional (3D) photography was
obtained before alpelisib administration. Each HNLM subject
was categorized by HNLM stage.
38
Each participant received
50 mg alpelisib per day. Participants completed a daily
medication diary to document adherence, medication toler-
ance, and adverse events. Parent report and/or self-report
questionnaires were administered and standard clinical
photography was obtained at clinical follow-up visits, which
occurred monthly.
39
Monthly laboratory testing consisted of
complete blood count and differential, coagulation studies,
blood glucose, HbA1C, electrolytes, renal function, liver
function tests, and urinalysis. Areas of concern, such as the
airway, were observed using endoscopy. MRI was obtained
every 6 months and 3D photos every 3 months. MRI se-
quences for each individual at each timepoint were registered
in 3D Slicer software (slicer.org). The registered multimodal
images were segmented using a custom software tool devel-
oped in MATLAB and 3D Slicer to quantitate HNLM volume
and changes in composition. Facial and cranial landmarks
were used to identify a consistent region of interest for
different time points. Serial 3D facial images were used to
measured facial volume change. Facial images were regis-
tered in 3D Slicer software, in which facial measures from
known landmarks (ie, nasion, menton, tragi, medial canthi)
were used to create a facial mask for each timepoint.
Table 1 Genetic testing for each participant
Participant No. Sample Type Variant VAF% Test
1 Lesion (gDNA) PIK3CA p.E542K 1.5 VANseq NGS
1 Buccal brushing with paired plasma (gDNA) neg n/a Targeted PIK3CA sequencing
1 Lesion (gDNA) PIK3CA p.E542K 0.56 ddPCR
2 Lesion (gDNA) PIK3CA p.E542K 6.0 VANseq
2 Blood (gDNA) PIK3CA p.E542K neg ddPCR
2 Cyst fluid (cfDNA) PIK3CA p.E542K 0.73 ddPCR
2 Cyst fluid pellet (cfDNA) PIK3CA p.E542K neg ddPCR
2 Mucosa (gDNA) PIK3CA p.E542K neg ddPCR
2 Lesion A (gDNA) PIK3CA p.E542K 3.59 ddPCR
2 Lesion B (gDNA) PIK3CA p.E542K 3.46 ddPCR
2 Lesion C (gDNA) PIK3CA p.E542K 9.39 ddPCR
2 Lesion D (gDNA) PIK3CA p.E542K 4.37 ddPCR
2 Lesion E (gDNA) PIK3CA p.E542K 2.80 ddPCR
2 Lesion F (gDNA) PIK3CA p.E542K 2.05 ddPCR
2 Lesion G (gDNA) PIK3CA p.E542K 1.69 ddPCR
2 Muscle (gDNA) PIK3CA p.E542K 0.13 ddPCR
2 Skin (gDNA) PIK3CA p.E542K neg ddPCR
2 Fat (gDNA) PIK3CA p.E542K 0.23 ddPCR
3 Blood (gDNA) PIK3CA p.E545K neg ddPCR
3 Cyst fluid (cfDNA) PIK3CA p.E545K 1.52 ddPCR
3 Cyst fluid pellet (cfDNA) PIK3CA p.E545K neg ddPCR
4 Lesion (gDNA) PIK3CA p.E545K NR Targeted PIK3CA sequencing
4 Blood (gDNA) PIK3CA p.E545K neg ddPCR
5 Lesion (gDNA) PIK3CA p.H1047R NR VANseq NGS
5 Lesion A (gDNA) PIK3CA p.H1047R 44.77 ddPCR
5 Lesion B (gDNA) PIK3CA p.H1047R 23.18 ddPCR
5 Lesion C (gDNA) PIK3CA p.H1047R 18.78 ddPCR
5 Lesion D (gDNA) PIK3CA p.H1047R 10.62 ddPCR
5 Lesion E (gDNA) PIK3CA p.H1047R 20.92 ddPCR
5 Lesion F (gDNA) PIK3CA p.H1047R 13.01 ddPCR
5 Lesion G (gDNA) PIK3CA p.H1047R 16.45 ddPCR
5 Lesion H (gDNA) PIK3CA p.H1047R 22.29 ddPCR
5 Muscle (gDNA) PIK3CA p.H1047R 16.87 ddPCR
5 Skin (gDNA) PIK3CA p.H1047R 8.83 ddPCR
5 Nevus (gDNA) PIK3CA p.H1047R 10.20 ddPCR
5 Blood (gDNA) PIK3CA p.H1047R neg ddPCR
Available sample types included tissue from lesion collected via biopsy, buccal brushing, plasma sample, cyst fluid, and cyst fluid pellet.
cfDNA, cell-free DNA; ddPCR, digital droplet polymerase chain reaction; gDNA, genomic DNA; n/a, not applicable; neg, negative; NGS, next-generation
sequencing; VAF, variant allele fraction; VANseq, Vascular ANomalies sequencing panel.
2320 T.L. Wenger et al.
Additional information regarding this imaging and software
tool can be found in Konuthula et al (2022).
40
Race and
ethnicity was reported by parents of each participant.
Results
Patients
Two groups of patients are described, including those with
HNLM (group 1, n=4) and PROS (group 2, n=1). The
medical and surgical course for each patient before and after
the initiation of alpelisib is provided in detail. Serial photo-
graphs of patients during alpelisib treatment are shown
(Figure 1). Images from MRI (Figure 2) and 3D photos
(Figure 3) are shown with facial volumes. Intraoral and
endoscopic photos are shown when used for clinical assess-
ment (Figure 4). Genetic testing for each participant is sum-
marized in Table 1.
All individuals were adherent to medical therapy for at
least 9 months and did not report any adverse events in
symptom diaries with the exception of 1 patient with
pre-existing diagnosis of eczema having worsened while on
therapy. Screening bloodwork identified mild hyperglyce-
mia (random blood sugar 116, fasting 102) on 1 measure-
ment for 1 individual. Individuals’parents and evaluating
clinicians observed improvement in multiple areas in each
patient. Facial volumes as measured by serial 3D images
were reduced in all subjects (Figure 3). Serial MRI analysis
of normalized imaging data showed a reduction in malfor-
mation volume in all subjects (Figure 2). Percentage
reduction in MRI and 3D clinical photography by timepoint
can be found in Supplemental Figure 1. Symptoms ques-
tionnaires were administered at baseline (time 0), after 3
months and after 6 months of initiation of therapy. When
present, symptoms decreased or resolved for each partici-
pant on therapy (Supplemental Figure 2).
Patient summaries
Group 1: HNLMs
Patient 1 is a now 2-year-old White and non-Hispanic fe-
male born at 39 weeks gestation, with a stage II microcystic
HNLM (unilateral suprahyoid). After birth, it was noted that
the left face was larger than the right side. She was other-
wise healthy without difficulty in breathing or feeding.
Initially left upper lip fullness showed no lip tissue abnor-
malities on ultrasound. Beckwith-Wiedemann syndrome
testing result was negative. Over 2 years, the asymmetry
became more prominent. She also developed lesions on the
buccal mucosa of the affected side, which caused her
discomfort. The primary reasons for electing to start alpe-
lisib treatment were her worsening facial asymmetry and
desire to limit continued progression as well as discomfort
and bleeding from the lesions on her buccal mucosa.
Traditional therapies, including sclerotherapy and/or sur-
gery, were anticipated to have limited effectiveness and
significant morbidity if she were to need intervention with
increasing severity of facial and lip asymmetry. Targeted
PIK3CA sequencing from genomic DNA isolated from
buccal brushing was negative. Left upper vestibulobuccal
sulcus lymphatic malformation and adjacent upper lip
overgrowth were noted. Next-generation sequencing using
genomic DNA from affected buccal tissue (VANseq panel)
was performed, and an activating PIK3CA variant was
found, NM_006218.4:c.1624G>A, p.E542K, which was
also later detected using ddPCR. (Table 1) Histology
showed HNLM features. She was started on alpelisib.
Baseline MRI showed left upper lip HNLM that became
significantly smaller at the sixth month MRI (Figure 2Aa
Figure 1 Clinical photos at alpelisib treatment initiation and after at least 6 months of treatment. A-E. Participants 1 to 5 are shown
from left to right with duration of alpelisib therapy at time of most recent photo.
T.L. Wenger et al. 2321
and b). However, on MRI, her total facial volume increased
by 10%. Over 11 months of therapy, facial volume, as
measured with 3D imaging, decreased from 567 cm
3
to
566 cm
3
(Figure 3A). After 11 months on therapy, her facial
asymmetry nearly normalized (Figure 1A). She has not had
any noted adverse events.
Figure 3 Three-dimensional (3D) facial photos with facial masks in participants 1 to 5, from left to right, after at least 6 months of
alpelisib therapy. Baseline anterior–posterior and oblique 3D images with accompanying facial masks are on the left and images after 6 or
more months of therapy are on the right. A. Participant 1: baseline facial volume =567 cm
3
; facial volume after 9 months of therapy =566
cm
3
. Note the reduction of left upper lip and cheek thickness. B. Participant 2: baseline facial volume =670 cm
3
; facial volume after 12
months of therapy =647 cm
3
. Note the reduction of right neck, cheek, and chin fullness thickness. C. Participant 3: baseline facial volume =
1111 cm
3
; facial volume after 6 months of therapy =887 cm
3
. Note the reduction of cheek thickness. D. Participant 4: baseline facial
volume =1412 cm
3
; facial volume after 9 months of therapy =1350 cm
3
. Note the reduction of cheek thickness. E. Participant 5: baseline
facial volume =710 cm
3
; facial volume after 12 months of therapy =614 cm
3
. Note the reduction of left upper lip and cheek thickness.
Figure 2 Select MRI scans in participants 1 to 5 before alpelisib. On left, a is baseline and on right, b is after at least 6 months of alpelisib
treatment. For participants 1 to 4, coronal images are superior and axial are inferior. For participant 5, (a, b) sagittal images are superior, and axial
are inferior. Aa, b. Participant 1. Note the reduced size and fluid content (bright white signal) of left upper lip and cheek malformation.
Ba, b. Participant 2. Note the reduction of fluid signal and size in coronal images. Ca, b. Participant 3. Note the size reduction in the cheek and
parotid region. Da, b. Participant 4. Note the reduction in size and fluid signal in the coronal images. Ea, b. Participant 5. Note the reduction in fat
in cheek and neck.
2322 T.L. Wenger et al.
Patient 2 is a now 5-year-old Hispanic female of Asian and
Latinx ancestry with a right sided stage III microcystic HNLM
(unilateral suprahyoid and infrahyoid). She was born via ex
utero intrapartum treatment procedure owing to prenatal
HNLM identification and concern for airway compromise.
There was transient difficultyinfeeding.Inthefirst 3 months
of life, sirolimus and sclerotherapy were used without clinical
benefit. At 12 months of age, intermittent malformation
swelling associated with respiratory illnesses began. Sirolimus
was tried again after age 2 years but quickly discontinued
because of mouth sores. Operative airway endoscopy and
imaging at 2.5 years of age showed significant distortion/
overgrowth of the right neck, pharynx, and oral structures and
were associated with obstructive sleep disturbance (Figure 4).
The right tonsil was larger than the left, and she underwent
adenotonsillectomy for intermittent snoring. At 2 years 9
months, she underwent extensive malformation excision with
parotidectomy, neck dissection, and floor of mouth resection.
There was persistent postoperative lymphorrhea and
continued asymmetry of the right face and facial skeleton.
Dental malocclusion with an anterior open bite and floor of
mouth swelling/pain/bleeding/macroglossia remained.
Postoperative marginal mandibular nerve weakness resolved
over a year and her speech had decreased intelligibility. At 4
years 2 months, her facial swelling worsened, including the
floor of mouth, impairing oral intake. A 2 cm ×3cm
cystic base of tongue swelling was identified, causing
partial airway compromise. Next-generation sequencing via
the VANseq panel using genomic DNA from malformation
tissue confirmed activating variant in PIK3CA,NM_0
06218.4:c.1624G>A (p.E542K), which was also later detec-
ted in cell-free DNA from cyst fluid using ddPCR.
Alpelisib was initiated at 4 years of age. In the first 3
months of therapy, facial/intraoral swelling and pain
decreased, speech intelligibility improved, and oral bleeding
stopped. After 8 months of treatment, midfacial/upper neck
were obviously decreased and oropharyngeal/floor of mouth
swelling was resolved, and tongue size and mobility
approached normal (Figure 1B). MRI determined malfor-
mation volume decreased by 23% over 10 months
(Figure 2Ba and b). After 12 months on therapy, facial
volume, as measured from 3D imaging, decreased from 670
cm
3
to 647 cm
3
(Figure 3B). She did experience worsening
of chronic eczema, prompting initiation of triamcinolone.
No other adverse events were noted.
Patient 3 is a now 3-year-old non-Hispanic male of White
and Asian ancestry with a bilateral stage V mixed-type
HNLM (bilateral suprahyoid and infrahyoid with medias-
tinal involvement). He was born via ex utero intrapartum
treatment procedure at 35 weeks because of prenatal HNLM
diagnosis and concern for airway compromise. MRI at 2
days of age showed extensive stage V HNLM. Extubation to
CPAP was performed at 2 weeks of age. Supraglottic mal-
formation obstructing the laryngeal inlet impaired ventila-
tion, and even with a partial supraglottoplasty, reintubation
was necessary. Sirolimus and aspirin were initiated.
12
Extubation to CPAP and then high flow oxygen was suc-
cessful at 7 weeks of age. Direct laryngoscopy at 2 months
of age showed persistent epiglottic swelling from malfor-
mation. PIK3CA NM_006218.4:c.1633G>A; p. E545K
37
was identified from cell-free DNA from aspirated malfor-
mation cyst fluid using ddPCR. Neonatal intensive care unit
discharge to room air occurred at 3 months of age, with
primary feeding via nasogastric tube. Gastrostomy tube was
placed at 9 months of age. Repeat MRI at 6 months and 23
months of age showed a similar HNLM appearance. Siro-
limus was discontinued in preparation for alpelisib therapy.
During the 3-week sirolimus hiatus, facial swelling and
snoring increased (Figures 1C and 4B). After 3 months on
alpelisib, facial swelling decreased and snoring ceased.
Airway endoscopy after 6 months of therapy showed normal
laryngeal appearance (Figure 4B). After 8 months of ther-
apy, facial/neck swelling continued to decrease, speech
intelligibility improved, and he could play normally without
malformation pain and swelling (Figure 1C). Baseline MRI
showed facial and pharyngeal swelling from the HNLM that
was reduced in volume by 6% over 6 months (Figure 2Ca
and b). During the same time, facial volume, as measured
using 3D imaging, decreased from 1111 cm
3
to 887 cm
3
(Figure 3C). There had been no adverse events.
Figure 4 Upper airway endoscopy photos from participants 2 to 4 at baseline (left) and after at least 6 months of alpelisib (right).
A. Participant 2: note swelling in pharyngeal wall narrowing the airway (left) and increased glottic visibility (right). B. Participant 3: note
supraglottic mucosal swelling (left) reduced after 6 months of alpelisib therapy (right), allowing easy glottic visualization. C. Participant 4:
note total distortion of laryngopharyngeal airway, with the epiglottis completely distorted by malformation edema, completely obscuring the
glottic (left). After 6 months of alpelisib, the epiglottis is visible and the glottic airway is patent (right).
T.L. Wenger et al. 2323
Patient 4 is a now 12-year-old non-Hispanic White in-
dividual, who was born with a bilateral stage V microcystic
HNLM (bilateral suprahyoid and infrahyoid with medias-
tinal involvement), assigned female sex at birth, who uses
they/them pronouns. This malformation was treated with 19
surgical procedures, including tracheostomy, gastrostomy
tube, numerous operative airway endoscopies, bilateral neck
dissections and parotidectomies, adenotonsillectomy, dental
procedures, and hiatal herniorrhaphy. Before age 3 years,
the patient had long hospitalizations associated with pro-
found T cell lymphocytopenia, recurrent painful HNLM
inflammation/swelling, and hypoventilation from tracheot-
omy tube dysfunction requiring prophylactic antibiotics.
None of these symptoms resolved with dietary and medical
therapy, and it was suspected that sirolimus worsened daily
oral bleeding. These medical problems had significant ef-
fects on their social and emotional well-being. At the age of
12 years, ongoing daily chronic oral bleeding resulted in
unrecognized anemia and high output cardiac failure,
necessitating transfusion. Their mouth had diffusely
swollen, inflamed, bleeding gingiva and tongue mucosa,
with poor dental hygiene and a large anterior open bite
making normal mastication and mouth closure impossible.
Upper airway exam revealed diffuse mucosal malformation
bleeding and extensive pharyngeal and supraglottic edema
from lymphatic malformation that completely distorted
normal laryngopharyngeal landmarks (Figure 4). Supple-
mental feedings via gastrostomy tube were necessary. Next-
generation sequencing of genomic DNA from affected tis-
sue using VANseq panel revealed a pathogenic change in
PIK3CA (NM_006218.4:c.1633G>A, p.E545K).
Alpelisib was begun at 12 years of age. After 1 month of
therapy, oral bleeding, macroglossia, and gingival edema
were reduced, facial swelling decreased, and hemoglobin
was stable. At 6 months on therapy, face swelling and
pharyngeal and oral bleeding were further reduced, pain was
absent, and speech intelligibility improved. The patient
stated that there was more pharyngeal space, easier breath-
ing with tracheotomy capping and easier swallowing. After
9 months of alpelisib therapy, endoscopy identified only a
focal source of pharyngeal bleeding, a grade 1 laryngeal
view, with normal appearing aryepiglottic folds and glottis
(Figure 4C). These changes continue at 13 months of
alpelisib therapy (Figure 1D). Baseline MRI showed facial
and neck swelling from HNLM that was reduced by 20%
over 6 months of alpelisib therapy. (2Da and b). After 9
months on therapy, facial volume, as measured using 3D
imaging, decreased from 1412 cm
3
to 1350 cm
3
(Figure 3D). Mild hyperglycemia (random blood sugar 116
mg/dL, fasting blood sugar 102 mg/dL) occurred once, but
otherwise there were no adverse events.
Group 2: PIKC3A-related overgrowth spectrum
Patient 5 is a now 5-year-old Hispanic Mexican female who
was born at 36 weeks in Mexico with what was thought to
be a left-sided face/neck HNLM. She was discharged to
home at 24 hours of life. Left facial/neck enlargement and
left auriculomegaly persisted and progressed, causing
feeding and breathing difficulty. Her parents sought medical
care for her worsening respiratory distress in Mexico, and
sinusitis was diagnosed. As her ventilatory status deterio-
rated, care was sought in the United States. While en route
on a commercial aircraft, in-flight respiratory distress
prompted an urgent landing and emergent tracheostomy. Per
report, significant glottic obstruction by soft tissue made
endotracheal intubation impossible. Her respiratory status
and feeding improved after tracheostomy and she returned
to Mexico. At 9 months of age, she presented at Seattle
Children’s Hospital Emergency Department for care. Sig-
nificant left facial/neck soft tissue and bony overgrowth with
a massively enlarged left tonsil, left auriculomegaly with ear
canal occlusion, and left facial nevus sebaceous were noted.
MRI result was consistent with FIL. Decannulation was
possible at 11 months of age after sequential left tonsillec-
tomy, lingual tonsillectomy, and supraglottoplasty. To
further reduce extrinsic upper airway compression at 12
months of age, she underwent total left parotidectomy with
buccal dissection. Next-generation sequencing of genomic
DNA from affected tissue via VANseq panel revealed
NM_006218.4:c.3140A>G, p.H1047R in PIK3CA. Over
the next 2 years, the left facial asymmetry continued to in-
crease internally, the mouth and oropharynx was largely
occluded by her enlarged left tongue, and left skeletal
malocclusion worsened lip closure, causing drooling.
Normal talking and mastication were impossible, prompting
concerns for developmental delay.
Alpelisib was begun at age 3 years. One month after
initiating therapy, there was evidence for facial shrinkage
(ie, left nasolabial fold, enlarged left palpebral fissure, patent
left ear canal). Continued improvement occurred during the
first 25 months of therapy, including reduced soft tissue
asymmetry and sebaceous nevus pigmentation and
improved mouth closure and tongue symmetry and motion.
Functionally, she had cessation of drooling and normaliza-
tion of speech, hearing, and airway patency (Figure 1E).
Baseline MRI showed extensive facial asymmetry from FIL
that was reduced by 13% over 24 months (Figure 2Ea and
b). After 12 months on alpelisib, facial volume, as measured
with 3D imaging, decreased from 710 cm
3
to 614 cm
3
(Figure 3E). There is continued facial skeleton asymmetry
and residual auriculomegaly. She has had no adverse events.
Discussion
Individuals with PIK3CA-associated head and neck disease
present management challenges that vary with lesion extent
and treatment efficacy. Although localized HNLM can
resolve or respond to conservative management, individuals
with extensive and infiltrative malformations traditionally
have suboptimal outcomes.
41
Common medical complica-
tions of head and neck PIK3CA disease were seen in our
cohort, including acute and/or chronic respiratory failure,
feeding difficulties, hearing loss, mouth pain, speech
2324 T.L. Wenger et al.
problems, malocclusion, vision loss, and distortion of the
developing facial skeleton along with cosmetic conse-
quences. Localized debulking procedures or sclerotherapy
are often effective for localized PIK3CA-associated
lymphatic malformations and overgrowth in other parts of
the body, but infiltrative malformations in areas of critical
function (ie, pelvis, extremity joints, etc) are also difficult to
treat completely. HNLM and head and neck PROS often
require surgical interventions (eg, tracheostomy, gastro-
stomy tube, jaw surgery), as well as speech therapy, feeding
therapy, orthodontic treatment, hearing accommodations,
and psychological support for the effect of their physical
differences on their social interactions. This early study
shows the effectiveness of alpelisib on a wide spectrum of
problems encountered by children with head and neck
PIK3CA-associated conditions.
Alpelisib was first reported as a well-tolerated and
effective treatment for PROS in 2018.
32
Although most re-
ports have included adults and/or individuals with CLOVES
phenotype, there are some individuals with HNLM who
have been described. Delestre et al
42
reported a cohort with
PROS, including a 15-year old with tongue involvement
(c.3140A>G; p.His1047Arg) and 27-year old with facial
involvement (c.1624G>A; p.Glu542Lys) that resulted in
decrease in volume with alpelisib treatment. Venot et al
32
reported a series of individuals with PIK3CA associated
disease (mostly CLOVES phenotype) that included a 5-year
old with facial overgrowth due to PIK3CA (c.3140A>G;p.
His1047Arg) who had other failed therapies and noted
41.3% reduction in facial mass volume after 6 months of
alpelisib treatment. They also reported a 16-year old with
megalencephaly-capillary malformation syndrome and
facial asymmetry associated with PIK3CA (c.1624G>A;
p.Glu542Lys) who had a 31.3% reduction in facial volume
with alpelisib. Raghavendran et al
43
reported a series of
individuals treated with alpelisib, including a 14-year old
with facial overgrowth due to PIK3CA H1047R (c.3140A>
G;p.His1047Arg) who had decrease in facial asymmetry and
improvement in eye opening after initiation of alpelisib. The
absolute improvement attributable to alpelisib alone is
challenging to assess because there were also 3 surgical
procedures during the study period. Two additional partici-
pants in that series had widespread overgrowth with facial
involvement. The first was a 42-year old man with PIK3CA
(c.3139C>T;p.His1047Tyr)-associated KTS, whose im-
provements on alpelisib included subtle improvements in
nasal overgrowth. The second was a 19-year old with KTS
that included facial asymmetry (PIK3CA c.311C>T;p.
Pro104Leu). Reduction in girth of upper and lower ex-
tremities was reported but no comment on facial asymmetry
was found.
43
Alpelisib has also been reported as effective in
the treatment of non-HNLM PIK3CA-related dis-
eases.
33,34,42-46
Morin et al
46
reported positive response in 2
infants younger than 1 year of age, one of whom had
hemimegalencephaly in addition to extensive lower ex-
tremity involvement (PIK3CA c.3132T>A, p.Asn1044Lys).
There was an inflection in head circumference and
improvement of seizures, although effect on cheek asym-
metry was not reported. Overall, these prior reports suggest
that alpelisib is effective in PIK3CA-related diseases, with
most reported individuals being adolescents or adults.
Younger reported individuals have had excellent treatment
response and lack of progression, suggesting earlier initia-
tion of treatment may have the potential for better clinical
outcomes.
Airway obstruction is a major source of morbidity and
mortality in large HNLM. In this report, 3 patients with
significant HNLM induced airway obstruction had near-
resolution of this obstruction with alpelisib. Patient 4 had
a tracheostomy in infancy and long hospital stays along with
persistent laryngopharyngeal airway obstruction. Alpelisib
treatment resulted in an unobstructed view of the upper and
laryngeal airway. It is anticipated that this improvement will
allow tracheotomy decannulation, often impossible in stage
V HNLM. Tracheostomy was being considered for patient 2
because of acute and chronic airway obstruction occurring
with respiratory illness. Alpelisib therapy dramatically
improved upper airway patency therefore tracheostomy was
unnecessary. Patient 2 had a combination of invasive and
medical therapies before alpelisib. How these therapies
affected alpelisib efficacy is unknown. Interestingly, other
than endoscopic airway procedures, patient 3 had no inva-
sive therapy before alpelisib therapy and medical treatment
has been successful in preventing tracheostomy. Because
this patient had a stage V HNLM, without targeted medical
therapy, it is likely that a tracheostomy would have been
necessary. Patient 1 had a localized HNLM not affecting the
airway. Within 6 months of age, patient 5 had an acute
airway emergency and tracheotomy from an undiagnosed
overgrown tonsil. Alpelisib therapy improved upper airway
patency and the ability to speak, but it is unclear if earlier
treatment would have prevented this overgrowth.
Sleep disordered breathing because of intermittent airway
compromise is another common and important symptom in
stage III-V HNLM and other large PIK3CA-associated head
and neck overgrowth conditions. Patients 1 to 3 all had
resolution of symptoms of sleep disturbed breathing after
taking alpelisib for 1 to 2 months. Reduction of secondary
airway compression from HNLM is probably associated
with reduction in facial volume. Intrinsic airway swelling
reduction in the base of tongue and laryngeal malformation
induced swelling were also seen on endoscopy and MRI in
patients 2, 3, and 4. Further study is necessary to understand
the significance of these findings, which have not been
described with sirolimus or other types of medical therapy.
Improvement in speech and swallowing was seen in
patients 2 to 5. These patients either had a gastrostomy tube
and/or oral dietary modification with chronic drooling.
Drooling resolved and a more normal diet was begun in all
these patients. This improvement seems multifactorial, with
increased pharyngeal patency, better tongue and pharyngeal
motion, and reduction of oral and pharyngeal mucosal
inflammation. Speech seemed to also be helped by these
factors and an enlarged laryngeal airway. This swallow and
T.L. Wenger et al. 2325
speech improvement seems unique to alpelisib. Dental
malocclusion did not change with alpelisib use, but our
study period was short. Certainly, tongue symmetry, oral
pain, floor of mouth swelling, bleeding, and gingival edema
were all improved in our patients.
Although prior studies have used MRI for measurement
of volumetric reductions in affected tissue, this manuscript
shows the use of 3D photography may also be a reasonable
alternative that is more cost-effective and does not require
sedation. A major limitation of this study is a short treatment
period, the lack of placebo control and randomization. We
think it is unlikely that the responses in our alpelisib patients
occurred by chance as part of the natural history of the
disorders.
In this study, volumetric analysis and clinical symptoms
were used to measure response to treatment. The VAF
varied widely at a single timepoint for participants 2 and 5
when tissue was sampled from different parts of the affected
region, and blood was consistently negative, limiting our
ability to use VAF as a biomarker for treatment response.
Future studies are needed to determine if VAF correlates
with treatment response.
There are many unanswered questions surrounding tar-
geted medical therapy for head and neck PIK3CA-associated
conditions in children. Future studies are needed to determine
the best dosing for children. In this study, all children received
50 mg daily by mouth per the Novartis expanded access
protocol for alpelisib although the weight-based dosing was
substantially different for our youngest and oldest patients.
Importantly, there were no significant adverse events in any
of our treated patients, and all patients had significant
improvement. This suggests that there may be a wide thera-
peutic index for this medication in children for the treatment
of PIK3CA-associated disorders of the head and neck.
Clinical use of alpelisib
Alpelisib was recently approved by the FDA for use in in-
dividuals aged 2 years or older with severe disease. How-
ever, the data from our cohort and other previously reported
individuals suggest that wider use might be beneficial. The
threshold that should be used for initiation of alpelisib are
unclear, but individuals with PIK3CA induced HNLM have
unique dysfunction from persistent overgrowth that affect
breathing, dental occlusion, soft tissue swelling, and
mucosal inflammation causing pain and bleeding. Targeted
medical therapy in these individuals seem to stop or reduce
facial and pharyngeal tissue overgrowth in HNLM. The
standard tools available for therapy include surgeries that are
not effective in stopping the overgrowth that is responsible
for many common symptoms of HNLM. Laryngeal and
pharyngeal involvement can lead to airway obstruction and
sleep disordered breathing, oral mucosal involvement can
cause bleeding, pain, and issues with articulation and
swallowing. Airway obstruction in HNLM is difficult to
address surgically, aside from tracheotomy when severe.
These difficult to treat overgrowth induced symptoms and
dysfunction should be balanced with risk of adverse events.
Across studies, there were few adverse events noted in
pediatric patients, but future studies are needed to better
understand the long-term consequences of alpelisib therapy
and whether its use prevents development of severe disease
with early initiation.
Data Availability
Because all data in this manuscript are specific to patient
responses to therapy for which privacy rules may apply,
requests for data should be directed to the corresponding
author, who can provide de-identified data in accordance
with privacy rules.
Acknowledgments
We acknowledge figure preparation by Eden Palmer and 3D
image acquisition by Erik Stuhaug. This study was funded
by the US National Institutes of Health under National
Heart, Lung, and Blood Institute (NHLBI) grants
F32HL147398 (to K.Z.) and R01HL130996 (to J.T.B.),
BurroughsWellcome Career Award for Medical Scientists
1014700 (to J.T.B.), Pilot Award Support Fund through
Seattle Children’s Research Institute, Excellence in
Research New Investigator Award through the Seattle
Children’s Research Institute (J.B.-V.), Research Integration
Hub (R.A.B.), and a Seattle Children’s Hospital Guild As-
sociation Funding Focus Award (to J.A.P.).
Author Information
Conceptualization: J.P.D., R.A.B., J.A.P., T.L.W.; Data
Curation: R.A.B., C.B., J.A.P., E.M., E.L., S.G.; Formal
Analysis: R.A.B., M.B., J.P.D., T.L.W., E.M., J.N.P., M.D.,
J.T.B.; Funding Acquisition: J.A.P., J.T.B.; Investigation:
G.M.S., R.A.B., J.T.B., K.Z., D.M.J., S.D.F., V.D., J.B.-V.,
J.A.P., T.L.W.; Methodology: R.A.B., M.B., J.N.P., M.D.,
J.T.B., K.Z., D.M.J., V.D., E.M., T.L.W.; Project Admin-
istration: S.G., E.L., A.K.; Resources: R.A.B., J.A.P.; Su-
pervision: R.A.B., M.B., J.A.P., E.M., J.T.B.; Validation:
R.A.B., M.B., E.M., J.A.P.; Writing-original draft: T.L.W.,
J.A.P.; Writing-review and editing: G.M.S., R.A.B., J.P.D.,
M.B., C.B., S.G., E.L., J.B.-V., J.T.B., E.M., J.N.P., J.A.P.,
T.L.W.
Ethics Declaration
This study was reviewed by the Seattle Children’s Hospital
Institutional Review Board and was approved under ID
2326 T.L. Wenger et al.
STUDY00002044. Informed consent was obtained from all
families. Written consent was obtained for patient infor-
mation, photographs, and images to be shared.
Conflict of Interest
R.A.B. is a cofounder and holds a financial interest of
ownership equity with Wavely Diagnostics, Inc. and Eigen
Health, Inc. He is a consultant and stockholder at SPIWay,
LLC. These are not related to this study. All other authors
declare no conflict of interest.
Additional Information
The online version of this article (https://doi.org/10.1016/j.
gim.2022.07.026) contains supplementary material, which
is available to authorized users.
Affiliations
1
Division of Genetic Medicine, Department of Pediatrics,
University of Washington School of Medicine, Seattle, WA;
2
Center for Clinical and Translational Research, Seattle
Children’s Research Institute, Seattle, WA;
3
Division of
Pediatric Otolaryngology–Head and Neck Surgery, Uni-
versity of Washington School of Medicine, Seattle, WA;
4
Center for Developmental Biology and Regenerative
Medicine, Seattle Children’s Hospital, Seattle, WA;
5
Department of Otolaryngology–Head and Neck Surgery,
University of Washington School of Medicine, Seattle, WA;
6
Craniofacial Center, Seattle Children's Hospital, Seattle,
WA;
7
Interventional Radiology, Department of Radiology,
Seattle Children’s Hospital, Seattle, WA;
8
Division of
Neurology, Department of Pediatrics, Seattle Children’s
Hospital, Seattle, WA;
9
Investigational Drug Services,
Seattle Children’s Hospital, Seattle, WA
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