Keywords
overgrowth syndrome - PTEN gene - neuroimaging
Introduction
Cowden syndrome is an autosomal dominant genodermatosis described in 1963 by Lloyd
and Dennis. It represents the most common phenotypical presentation of phosphatase
and tensin homolog (PTEN) mutations.[1] The disease is characterized by multiple hamartomas, facial dysmorphism, mucocutaneous
lesions, and macrocephaly.
These patients have an increased risk of developing malignant tumors, especially of
the breast, thyroid, endometrium, kidney, and rectum.[2]
[3]
[4] The majority of mutations in this gene associated with PTEN hamartoma tumor syndrome
are loss of function mutations. Many studies have also described the association of
the PTEN gene with neurodevelopmental disorders and macrocephaly; in these last conditions
there is often the presence of an altered but functional gene product. The protein
plays an important role in regulating the duration of the cell cycle; in these patients,
cell cycle appears shorter but with a higher proliferation rate, a lower response
to stress with defects in migration, and differentiation of neuronal stem cells and
neuronal precursor cell.[5] The protein intervenes in the processes of dendritic arborization, in the formation
of synapses for neuronal circuits and in motor, memory, social interaction, and speech
functions, which appear altered in these patients.[5]
Case Presentation, Genetic Analysis, and Neuroimaging
Case Presentation, Genetic Analysis, and Neuroimaging
The patient, a 4-year-old girl, was evaluated for developmental delay. She was born
at term after regular pregnancy with the weight of 3,600 g, head circumference 34 cm.
Mother referred psychomotor development delay. At the clinical examination, we noted
macrocrania associated with normal height and weight for growth curves (50° pc for
age). As recommend in first line, we performed blood counts and complete biochemical
analysis (IGF-I, IGFBP-3, free T4, and TSH) with normal result. For the suspect of
a genetic syndrome because of the evidence of macrocrania and autistic disorders,
we underwent genetic analysis of genes associated with overgrowth syndrome (next-generation
sequencing gene panel). The analyses carried out the variant c.697c > T p.(Arg233*),
a heterozygous mutation in the PTEN gene that results in a premature stop codon. The
mutations was confirmed by Sanger sequencing. The variant is considered as “pathogenic”
according to the American College of Medical Genetics and it is described as a pathogenic
variant in different database (dbSNP, Clinvar, HGMD, LOVD, Franklin, Alamut, Varsome).
PTEN gene is a tumor suppressor gene located at chromosome 10q23.31, encoding for
a protein of 403-amino acid with lipid and protein phosphatase activities and predominantly
it is located in the cytoplasm. PTEN is the main antagonist of the phosphatidylinositol
3-phosphate kinase (PI3K)/protein kinase B (AKT) pathway by hydrolyzing phosphatidylinositol
3,4,5-triphosphate (PIP3) to phosphatidylinositol-4,5-bisphosphate (PIP2) and through
this activity PTEN plays an important role in cellular proliferation and differentiation,
in lipid and glucose metabolism and in regulation of many cellular functions.[6]
In the most differentiated and resting cells, the protein is also located in the nucleus
where PTEN has a role in chromosomal stability, DNA repair, and cell cycle regulation
and PTEN inactivation can lead to genomic instability, apoptosis, and failure to repair
DNA damage.[7] Loss of PTEN function can increase AKT activation causing cell proliferation and
survival, and it plays a role in tumor development and progression.
After decades of study on the PTEN gene, recent studies have identified a new isoform
of 173 amino-terminal extra amino acids that regulate mitochondrial energy metabolism.
Recognition of isoform of PTEN helps to understand the complexity of PTEN function
and it will advance our understanding on the role of PTEN in pathological processes.[8] Taking into account the multiple molecular effects of this protein, it is easy to
understand how the mutations of this gene can be correlated to the etiology of different
pathological conditions such as metabolic disorders, inflammatory and neurodegenerative
conditions, onset of neoplasms, and neurodevelopmental disorders.
Monoallelic mutations in PTEN gene are associated with a PTEN hamartoma tumor syndrome,
including Cowden syndrome, and with a hereditary form of autism associated with macrocephaly.
These conditions are autosomal dominant genetic disorders, and these disorders are
compatible with phenotypic spectrum of our patient.
We also performed a neuroimaging investigation ([Fig. 1]
[2]
[3]), showing anomalies previous reported in literature.[9] In particular, we noted prominent perivascular spaces, white matter abnormalities,
and frontal developmental venous anomalies in Cowden syndrome.
Fig. 1 Axial T2-weighted TSE magnetic resonance imaging (MRI). (A–B) Sagittal fluid inversion recovery (FLAIR) MRI. (C–D) show bilateral posterior periventricular deep white matter linear region (prevailing
in the right side) of high T2 signal with that attenuate fully on FLAIR due to prominent
perivascular spaces (arrows).
Fig. 2 White matter abnormalities in Cowden syndrome. Axial (A) and coronal (B) T2-weighted magnetic resonance images show increased T2 signal intensity on right
periventricular posterior region (circles).
Fig. 3 Frontal developmental venous anomalies in Cowden syndrome. Axial T1 (A) and sagittal T1 (B) postcontrast magnetic resonance imaging demonstrates right frontal developmental
venous anomalies (arrows).
Discussion and Conclusions
Discussion and Conclusions
Genetic, epigenetic, and hormonal factors play a role in abnormally excessive growth.
Overgrowth syndromes generally can present an increased risk of tumor predisposition
that necessitate prompt diagnosis and appropriate referral.[10] For the clinical practice, we can summarize the overgrowth diagnosis into three
phenotypes: prenatal, postnatal, and segmental overgrowth.[10]
The prenatal overgrowth includes newborns who are large for gestational age.[11] Common considerations include maternal diabetes and overgrowth syndromes such as
Beckwith–Wiedemann syndrome. Affected individuals may continue to show an accelerated
growth postnatally (pre- and postnatal overgrowth) or may grow at a normal pace with
length falling within 2 standard deviations (SDs) of the mean.
The postnatal overgrowth includes an accelerated growth pattern typically in childhood
or adolescence. It usually depend on endogenous hormone-dependent growth (thyroid,
growth hormone, sex hormones, or glucocorticoid). Other etiologies include familial
tall stature (constitutional tall stature), precocious puberty, obesity, Marfan syndrome,
homocystinuria, Klinefelter syndrome, and 47,XYY syndrome.[12]
Finally, the segmental overgrowth is confined to one or a few regions of the body,
such as macrocephaly in our case. Macrocephaly always requires special attention.
PTEN syndrome disorders (Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome, and Proteus-like
syndrome) are part of this group. As previous reported, PTEN is a phosphatase that
removes a phosphate from the second messenger phosphatidylinositol triphosphate and,
by doing so, inhibits the Akt (protein kinase B) pathway, a cardinal pathway of cell
proliferation and angiogenesis. In literature, studies report different manifestation
of segmental overgrowth syndrome. In particular, newborns with Bannayan–Riley–Ruvalcaba
have striking macrocephaly (≥4.5 SD), out of proportion to their birth weight and
length; those with Proteus-like presentation exhibit mosaic pattern of rapidly progressive
overgrowth of different tissue types; Cowden syndrome, rarely expressed in children,
associated with hamartomata and macrocephaly.[10] Typically, Cowden syndrome manifests mostly in second–third decade of life with
distinctive trichilemmomas (benign neoplasm derived from the outer root sheath epithelium
of the hair follicle), papillomatous papules (benign neoplasm of epithelium), and
acral and plantar keratosis seen in 99% of patients. Thus, an early diagnosis such
as our case is rarely reported, but it is important for the management including mucocutaneous
manifestations and cancer surveillance.
As reported in literature, cerebral white matter anomalies are present in Cowden syndrome.[9]
[13] The mechanism behind enlarged perivascular spaces in Cowden syndrome is not clear,
although they are seen in other genetic syndromes such as storage disorders (mucopolysaccharidosis).[9] PTEN has a role also in angiogenesis; thus, it frequently have vascular anomalies
such as our patient.
In conclusion, Cowden syndrome is a rare presentation in pediatric age, but it should
be suspected in case of macrocrania and developmental delay. A neuroimaging study
is important, because of the risk of malignancy associated. An early diagnosis in
pediatric age can modify the prognosis in adulthood.
