Contributors’ Statement Page
Drs. Hanson and Ghera conceptualized and designed the study, drafted the
initial manuscript,
and reviewed and revised the manuscript. Both authors approved the final
manuscript as submitted and agree to be accountable for all aspects of
the work in ensuring that questions related to the accuracy or integrity
of any part of the work are appropriately investigated and resolved.
Abstract :
An adolescent female with ventilator-dependent spinal muscular atrophy
type 1 (SMA-1) and megalencephaly-capillary malformation-polymicrogyria
(MCAP) syndrome had been struggling with recurrent small to large volume
hemoptysis for years secondary to complex arteriovenous malformations
(AVMs) in her lungs. Despite numerous embolizations, she continued to
experience hemoptysis from new AVMs. She was then started on sirolimus
(rapamycin) and remains hemoptysis-free for over 12 months.
To our knowledge, there are no known cases of SMA-1 with MCAP syndrome
and related complex vascular malformations successfully treated with
sirolimus.
Introduction :
SMA is an autosomal recessive genetic disorder caused by a mutation in
SMN1 gene, resulting in progressive degeneration of the spinal cord and
brainstem motor neurons.1,2
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
(PIK3CA ) encodes the p110α isoform of phosphatidylinositol
3-kinase (PI3K).3 Activating mutations inPIK3CA have long been linked to cancerous conditions and more
recently linked to non-cancerous conditions such as PIK3CA-related
segmental overgrowth spectrum (PROS).3 PROS is an
umbrella term that encompasses a heterogeneous group of rare,
non-cancerous yet debilitating congenital
conditions.3,4
One specific PROS presentation is MCAP syndrome, which typically
presents at birth with macrocephaly and hemihyperplasia and can be
progressive.5,6 Affected individuals can have
capillary malformations and consequent higher incidence of venous
thrombi.6
Sirolimus is an FDA-approved mammalian
target of rapamycin (mTOR) inhibitor.1 Its
antiproliferative, immunosuppressive and anti-angio/lymphangiogenic
properties are effective in decreasing pathologic growth and vascular
proliferation in children with lymphatic malformations,
lymphatico-venous malformations, and kaposiform
hemangioendotheliomas.3,4,5 It has been hypothesized
that the use of these mTOR inhibitors could be expanded to use as
therapeutic alternatives for patients with refractory vascular anomalies
such as those associated with PROS.4,5
To our knowledge, our patient is the first known case of SMA-1 in
association with MCAP syndrome. Treatment of complex AVMs such as those
associated with MCAP syndrome is difficult and may require
investigational therapies. Our patient was suffering from recurrent
hemoptysis episodes prior to resolution with oral sirolimus therapy.
Case Description :
An adolescent female with ventilator-dependent SMA-1 struggled for years
with recurrent small to large-volume hemoptysis. She underwent various
imaging studies, bronchoscopies, and interventional radiology (IR)
procedures, which identified bleeding sources to be complex AVMs in her
lung vasculature. The AVMs were attributed to her MCAP syndrome,
diagnosed by clinical signs and symptoms (large size at birth, skin
covered with capillary malformations-faded over time, right-sided
hemihyperplasia) and confirmed with PIK3CA gene mutation in
cultured skin fibroblasts.
Despite recurrent embolizations of appropriate blood vessels, she
continued to have hemoptysis not amenable to further IR interventions.
She was then started on sirolimus for management of her AVMs.
Sirolimus was initiated as twice daily enteral administration of 0.8
mg/m2 through her gastrostomy tube. The dose was titrated to target
trough levels of 10-15 ng/mL. The plan was to use this medication for
10-12 months while monitoring for side effects and improvement in signs
and symptoms. Given her comorbid conditions, we had to stop sirolimus
twice during the initial months. Co-administration of antifungal drugs
(voriconazole or posaconazole) for management of chronic paronychia lead
to supratherapeutic levels of sirolimus, so it was stopped for 3 months.
It was stopped again for two months in order for her to get an Ommaya
reservoir (spinal port) placement. Afterwards, she received
uninterrupted 12 months of sirolimus therapy per plan. She was
monitored for side effects related to bone marrow suppression, hepatic
or renal damage via regular complete blood counts (CBCs), liver function
tests (LFTs), creatinine and urine protein levels, respectively, which
remained normal. Serial computed tomography (CT) chest with contrast,
were obtained which showed significant improvement during the first 6
months [Figure 1] with stabilization of AVMs thereafter. She had no
further episodes of hemoptysis, and sirolimus was discontinued after a
duration of 12 months of treatment. Further plan is to continue to
monitor for her symptoms, repeat imaging if needed, and restart
sirolimus or, if possible, a similar newer drug like alpelisib with
lesser side effects, if symptoms reoccur.
Discussion :
SMA-1, also known as Werdnig-Hoffman Disease, is the most common form of
the disorder.1 Affected patients may appear normal at
birth prior to the development of symptoms - progressive hypotonia,
symmetric limb weakness/flaccid paralysis, poor head control, and
reduced/absent reflexes - by six months of age.1
PROS conditions are characterized primarily by asymmetric overgrowth
caused by mosaic-activating PIK3CA variants in tissues of
mesodermal origin.2 The PIK3CA mutations
identified in PROS are consistent with those identified in solid tumors,
the H1047R mutation in the catalytic domain being the most
common.2 Somatic PIK3CA mutations, on the other
hand, exist primarily in epithelial tissues and are mutations often
implicated in cancers.2
PIK3CA encodes the p110α catalytic subunit of
PI3K.3 This kinase is essential to growth factor
signaling and normal vascular development [Figure
2].4,5 The PI3K pathway is regulated by mTOR
[Figure 2].4,5 mTOR is a kinase that stimulates
protein synthesis, resulting in various cellular processes, including
cell proliferation and increased angiogenesis [Figure
2].8 Increases in mTOR signaling enhance expression
of vascular endothelial growth factor (VEGF), a primary regulator of
angiogenesis and lymphangiogenesis.5 Thus, mTOR plays
an integral role in the development of various vascular
anomalies.4,5 Activating somatic mutations inPIK3CA cause dysregulation of the PI3K pathway, leading to
physiologically inappropriate activation of protein kinase B (AKT) and
mTOR signaling with subsequent excessive/asymmetric tissue growth
[Figure 2].4 The pathologic proliferation in thesePIK3CA -mutated patients is referred to as PROS and can be further
characterized into various syndromic clinical presentations. Two
examples of PROS include congenital lipomatous overgrowth vascular
malformations-epidermal nevi-skeletal abnormalities (CLOVES) or our
patient’s diagnosis, MCAP, as described above.3
Laser ablation therapy is the current standard of care for treatment of
vascular anomalies in MCAP syndrome, but novel approaches are needed on
a case-by-case basis, like ours. Sirolimus has proved to be an
efficacious and safe treatment for the majority of complex vascular
anomaly patients.5 Recent clinical trials have
demonstrated its efficacy in these patients, some of which were known to
have elevated PI3K/AKT/mTOR signaling.5 This case
further supports and suggests that systemic sirolimus therapy decreases
morbidity associated with complex pulmonary AVMs in the setting of two
rare, coexisting syndromes. Further studies are required to assess
long-term treatment outcomes for specific disease phenotypes, optimum
length of treatment with sirolimus, and utility of newer drugs like
alpelisib.
Figure 1 : CT chest w/wo contrast (lung window). Coronal views
of posterior lung fields 8/2017 (Figure 1a), 10/2018 (Figure 1b) and
4/2019 (Figure 1c). Previously-visualized tiny nodular lesions (AVM) in
right and left lower lobes have significantly improved with sirolimus
therapy.
Figure 2 : Mode of action of sirolimus. pTEN: phosphatase
and TENsin homolog ; FKBP: FK506 (sirolimus) binding protein ;
SRL: sirolimus ; PI3K: phosphoinositide 3-kinase ; AKT:serine/threonine kinase also known as protein kinase B (pKB);
mTOR: mammalian target of rapamycin ; eIF4E: eukaryotic
translation initiation factor 4E ; S6: ribosomal
protein .4
References
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