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Mosaicism may be considered in sporadic cases; there should be a negative history in ancestral generations or siblings but offspring may be affected through gonadal mosaicism.
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A patchy distribution of cutaneous features and tissue overgrowth or disseminated disease that is mild should raise suspicion for mosaicism.
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Next-generation sequencing, or other methods for detecting low frequency alleles, of affected tissue is frequently necessary to identify the genetic basis of mosaic conditions.
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Drugs
Mosaic Disorders of the PI3K/PTEN/AKT/TSC/mTORC1 Signaling Pathway
Section snippets
Key points
PI3K/PTEN/AKT/TSC/mTORC1 signaling pathway and overgrowth
Cell growth is mediated by extracellular cues and may occur via increasing cell mass or cell division or by suppression of apoptosis. Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a central regulator of cell growth13 that is disrupted in many human disorders of cell proliferation, including cancers.4, 5, 13, 14, 15 Under normal conditions, mTORC1 is sensitive to inputs from diverse cellular and environmental cues (see Fig. 1), including the phosphoinositide-3-kinase (PI3K)
Mosaic-Only Oncogenes
It is widely regarded that strongly activating germline mutations in AKT1 and PIK3CA are lethal, with few reported exceptions.9, 26, 29 Mutations in these genes result in distinctive segmental, or asymmetric overgrowth syndromes that can involve the bone, muscle, adipose tissue, skin, and/or nerves and may be relatively stable (PIK3CA) or progressive (AKT1 or PIK3CA) in course.9, 26, 30, 31, 32 The severity of the overgrowth may range from a slightly enlarged digit to a gigantic limb.33, 34
Comparing phenotypes
Although these disorders are distinctive, there is overlap in the phenotypes associated with mutations of PIK3CA, PTEN, TSC1, TSC2, and AKT1, which may be expected given their common pathway and mosaic pathogenesis. Disorders of this axis may be broadly characterized by frequency of 1 or more of the following features: segmental overgrowth, hamartomas, or malignant tumors (Table 1). Because all 4 conditions are characterized by hamartomas, Table 2 contrasts the specific types of hamartomas
Timing of Mutations
Variation in the timing of postzygotic mutations may cause phenotypic variability, conferring a spectrum of disease burden. In TSC and PHTS, individuals with an early postzygotic mutation often have similar disease features and distribution of disease to those with a germline mutation.19, 20, 50, 59 More specifically, postzygotic mutations occurring before or after cell differentiation events may explain certain disease presentations. For example, a TSC2 mutation occurring during
Diagnosis of mosaicism
Clinical diagnosis alone is often difficult for these conditions, given substantial overlap of characteristic features. Although traditional genetic analysis of mosaic patients can be equally difficult, sampling the affected tissue, rather than blood, using deep sequencing methods seems to have greater diagnostic accuracy.11, 19, 22, 66, 67, 69, 70 For instance, studies suggest that up to 15% of patients with TSC may be mosaic; however, conventional sequencing methods may fail to detect low
Counseling for prognosis and management
The presence of seemingly benign skin findings or highly limited disease involvement may have greater clinical importance than is apparent. This example has been recently demonstrated in TSC, in which patients with mild clinically apparent disease in fact harbored serious internal manifestations that caused morbidity and, sometimes, mortality.12, 73 Thus, lifetime surveillance for brain, pulmonary and renal hamartomas is necessary for all patients with TSC, including those with mosaic mutations.
Summary
The mosaic disorders of the PI3K/PTEN/AKT/TSC/mTORC1 signaling pathway share a common axis but distinct mutations in this pathway are associated with highly variable clinical presentations that are recognizable. These clinical presentations should be genetically confirmed because each condition has unique implications for disease management. This common pathway may provide insight into treatment. For instance, oral mTORC1 inhibitors have shown to reduce the disease burden in TSC,74, 80 have
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Funding or Support: Dr J. Moss was supported by the Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute. Dr L.G. Biesecker and Dr K.M. Keppler-Noreuil were supported by the Intramural Research Program of the National Human Genome Research Institute. Dr T.N. Darling was supported by National Institutes of Health R01 AR062080. This research was also made possible through a Doris Duke Charitable Foundation Clinical Research Mentorship grant (#2014088).
Conflicts of Interest Disclosures: None reported.