Introduction
Congenital fetal neck tumors constitute exceedingly rare antenatal
conditions. Prenatal diagnosis is usually straightforward by detailed
sonographic examination. According to current literature these lesions
are categorized into different types.1–3 The most
frequently described subtypes of neck tumors comprise lymphangiomas,
followed by teratomas and hemangiomas.1 However, the
exact incidence of lymphangiomas remains unclear. It considerably varies
whether pre- or postnatal cohorts are analyzed. Prenatal data suggest an
estimated incidence of up to 1 in 1,000 live
births.2,4,5
Although lymphangiomas are non-malignant vascular malformations of the
lymphatic system and histologically mostly benign, extensive and
heterogeneous tumor masses may compress vital cervical structures, so
the final prognosis has been reported to be
poor.1,2,6,7
The clinical course of lymphangiomas is related to the type of lymphatic
malformation and varies from a mild symptomatic that tends to regress
spontaneously to an aggressively invasive growth into surrounding vital
structures.5 Spontaneous regression in the latter
cases is unlikely, but possible.4,8 By compressing
phenomena, polyhydramnios or airway obstruction can occur, a potentially
life-threatening event.5,6,8,9
Lymphatic malformations like lymphangiomas usually arise from the
defective embryological development of primordial lymphatic
structures.3,8,10 Recent data revealed that
lymphangiomas receive their growth stimuli by activating missense
mutations characterizing regional-located tumors in PIK3CA-Related
Overgrowth Spectrum (PROS).9,11–13
PROS encompasses a group of disorders that are predominantly
characterized by benign segmental overgrowth of several tissues with
vascular and lymphatic malformations. Caused by heterozygous, mostly
somatic mosaic-like pathogenic variants in the PIK3CA gene that arise
post-zygotically, affected patients may present with regional-located or
multiple-located findings.6,9,14,15 The clinical
picture strongly depends on the embryonic stage in which the causative
mutation occurred, as well as the tissue type affected by this
mutation.15 Specific somatic activating mutations in
the phosphatidylinositol-3-kinase/AKT/mTOR (PI3K-AKT-mTOR) pathway lead
to heterogeneous segmental overgrowth phenotypes.14The PIK3CA gene encodes the 110 kD catalytic alpha subunit (p110α) of
the PI3K protein complex, a lipid kinase of the PI3K-AKT-mTOR pathway, a
signaling pathway, which is crucially involved in the regulation of cell
proliferation, metabolism and survival as well as in angiogenesis.
Hence, PI3K plays a key role in cell growth and division, cell migration
and survival.6,9,16 An altered activity of PI3K leads
to uncontrolled cell division and as somatic mosaics, these mutations
may trigger the development of overgrowth syndromes with segmental
growth of several tissues with venous as well as lymphatic malformations
to varying degrees.6,9,13,16
Over the past years, cancer associated PIK3CA mutations have been also
reported to be responsible for a wide range of clinical benign
overgrowth disorders.6,17 Recent insights emphasize
the topicality of PROS disorders.9,13,18
Lymphangiomas, developed regionally located in the context of PROS, are
scarcely mentioned in the literature and informative case reports are
almost completely missing. While the acronym PROS is an umbrella term
for various clinical entities, even those entities itself, like
lymphangiomas, can morphologically resemble as a
chameleon.14
In the present report the prenatal and postnatal course of a fetus
suffering from a huge cervical lymphangioma within the PROS will be
delineated. We discuss the clinical picture to what is known from
current literature and focus on the targeted multidisciplinary approach
to establish the final confirmation of an activating missense
mutation-hotspot c.1633G>A;p.Glu545Lys identified by next
generation sequencing.