Vascular Anomalies

The chapter provides a description of the main anomalies characterized by excessive proliferation of the vascular tissue and the major syndromes associated with them. The predominant types of vascular anomalies are vascular tumors and vascular malformations. Vascular tumors are further subdivided in benign, locally aggressive, and malignant, according to the clinical course of the lesions, while vascular abnormalities are classified as simple (capillary, lymphatic, venous, arteriovenous, and arteriovenous fistula) or combined. For each subgroup of vascular anomalies, clinical presentation and diagnostic procedures are discussed, as well as pathogenic mechanisms and potential comorbidities. The management of vascular anomalies may be oriented to treat the aesthetic discomfort as well as the functional impairment and may involve both pharmaceutical and surgical approaches.

PIK3CA-Related Overgrowth Spectrum

Postzygotic mutations of the PIK3CA gene are associated with a series of clinical phenotypes characterized by segmental overgrowth and recently grouped under the term PIK3CA-related overgrowth spectrum (PROS). This chapter provides an overview of the clinical features shared by the phenotypes in PROS, including both the conditions with isolated features and the ones with syndromal presentation. The somatic overgrowth in cases with PROS is asymmetric, progressive, and “ballooning” in appearance and tends to involve predominantly the limbs, including fingers and toes, although the trunk and face are often affected as well. The tissues affected in the overgrowth can include all or some of these types: fibrous, adipose, vascular, nervous, and skeletal. Somatic gain-of-function mutations of PIK3CA cause activation of the PI3K-AKT pathway, leading to excessive cell growth and proliferation. Timing of PIK3CA mutations, tissue specificity, and type of mutation may play a role in the phenotypic variability of PROS.

Proteus Syndrome

Proteus syndrome is an exceedingly rare disorder, perhaps the least common of all overgrowth syndromes but one of the most distinctive because of its segmental nature and unrelenting progression. Proteus syndrome occurs sporadically and was the first of the segmental overgrowth syndromes found to be caused by somatic mosaicism. The discovery of an activating mutation in AKT1 by Les Biesecker and colleagues at the National Institutes of Health provided the initial molecular proof for somatic mosaicism in Proteus syndrome. Overgrowth in Proteus syndrome can involve nearly any tissue or part of the body. Presumably a germline mutation that would affect all tissues of the body would be lethal. Overgrowth of a tissue or a body part is the distinctive manifestation of Proteus syndrome but in most cases will be accompanied by other cutaneous, skeletal, vascular, or soft tissue findings. Although the possibility of an increased risk for developing neoplastic disease is a concern in any overgrowth disorder, this has not been demonstrated in Proteus syndrome.

Lateralized Overgrowth

The chapter discusses body asymmetry occurring as an isolated clinical feature or as part of well-characterized syndromes. The term “lateralized overgrowth” has been recently introduced to describe conditions characterized by disproportionate growth of one side of the body that might be caused by hemihyperplasia and/or hemihypertrophy. The chapter also provides a brief clinical overview of the major syndromes associated with lateralized overgrowth and discusses the molecular anomalies causing this disorder. Prognosis of conditions characterized by lateralized overgrowth varies according to the underlying cause. Treatment and management of conditions characterized by lateralized overgrowth mainly focus on tumor surveillance and management of eventual difference of limb length. Leg-length discrepancy can be associated with significant morbidity and can negatively influence the quality of life.

Malan Syndrome

The chapter discusses the clinical phenotype and the molecular abnormalities in Malan syndrome, an overgrowth condition caused by mutations in the NFIX gene. Overgrowth in Malan syndrome can be present at birth, especially in terms of large head circumference, and it continues after birth, although statural growth velocity decreases with age. The syndrome is also characterized by dysmorphic facial traits, skeletal abnormalities, intellectual disability, visual problems, and advanced bone age. This condition is allelic to another overgrowth disorder, Marshall-Smith syndrome, with which it shares several clinical features and should be considered in the differential diagnosis. The causative gene for both conditions, NFIX, encodes the nuclear factor one X-type transcription factor, which regulates the growth of several types of connective tissues.

Beckwith-Wiedemann Syndrome

This chapter provides a thorough overview of Beckwith-Wiedemann syndrome, which is considered to be the most common of the overgrowth syndromes and imprinting disorders. It starts with a description of the clinical aspects of the condition, including diagnostic criteria, differential diagnosis, risk of malignancy, and management. This is followed by an in-depth description of the genetic causes of the syndrome and of the molecular pathways involved in the pathogenesis of this disorder. The complexities of the etiology, which involves two neighboring loci, each one regulated by finely tuned imprinting mechanisms, are clearly delineated. The chapter also touches on the reported association between in vitro fertilization and risk of conceiving a baby with this syndrome.

Perlman Syndrome

This chapter describes Perlman syndrome, which is an autosomal recessive overgrowth syndrome that presents with a severe phenotype, usually resulting in early postnatal death. Overgrowth is extended to the internal organs, liver, pancreas, and especially kidneys, with histologic findings of focal hamartomas and nephroblastomatosis. These dysplasias predispose to the development of Wilms tumor, a very common occurrence in Perlman syndrome. The condition seems to be very rare, even though mild cases, if any exist, may go undiagnosed. The causal mutation affecting the DIS3L2 gene was discovered only recently and it is not known if this is the only causal gene.

Simpson-Golabi-Behmel Syndrome

Simpson-Golabi-Behmel syndrome was described independently by three groups of authors and eventually received its current designation by the author of this chapter. Among all the conditions described in this book, it is the only one to have X-linked inheritance, with possible expression in some carrier females. Therefore, the description of the clinical phenotype is subdivided into two parts, one pertaining to males, the other to females. Typically present in both affected males and females is a “coarseness” of the facial traits, in addition to a number of congenital malformations that can affect the heart, the diaphragm, and the skeleton. Differential diagnosis and recurrence risks are clearly delineated. The genetic cause is described in detail and the pathogenic mechanism is illustrated by an explanatory cartoon.

Sotos Syndrome

This chapter describes Sotos syndrome as a clinical entity characterized, in addition to overgrowth, by distinctive craniofacial manifestations that include macrocephaly, a tall forehead, and an elongated face with pointed chin. This clinical aspect is illustrated by photographs of patients. The differential diagnosis between Sotos and other overgrowth syndromes can be particularly difficult and is therefore described in detail, with the aid of a summary table. The genetic cause and inherent pathogenic mechanisms are clearly delineated. Even though malignancies are reported in less than 1% of patients with Sotos syndrome, this potential risk is not to be disregarded and is the object of a thorough discussion.

PTEN-Related Overgrowth Syndromes

Individuals carrying germline mutations in the tumor suppressor gene phosphatase and tensin homolog (PTEN) may present with diverse clinical phenotypes, grouped under the term of PTEN hamartoma tumor syndrome (PHTS). This chapter will focus on two PHTS conditions: Bannayan-Riley-Ruvalcaba syndrome and Cowden syndrome. The first condition is an autosomal dominant disorder characterized by macrocephaly, intestinal hamartomatous polyposis, vascular malformations, lipomas, hemangiomas, and genital freckling. Other features include developmental delay, hypotonia, and scoliosis. Cowden syndrome is also an autosomal dominant disorder, mainly characterized by multiple hamartomas and high risk of breast, thyroid, and other cancers. PTEN encodes the main inhibitor of the PI3K-AKT pathway, regulating cell growth and proliferation, and protein synthesis. Therefore, germline loss-of-function mutations in this gene lead to excessive growth, particularly affecting connective tissues. Detection of PTEN mutations is critical for clinical management and treatment strategies.