Overgrowth Syndromes, Diagnosis and Management

Summary

The systematic approach to the child with overgrowth aids in the standardization of the diagnostic pathway for these young patients, thereby expediting the diagnostic timeline, enabling rigorous monitoring, and delivering tailored therapeutic interventions.

Introduction

Overgrowth syndromes constitute a diverse group of clinical and genetically characterized conditions and have historically been distinguished by either an elevation in patient height, weight, and/or head circumference surpassing three standard deviations from the mean or exceeding the 99th percentile growth chart, in comparison to age and sex-matched controls. This classification has evolved over time to encompass a broader spectrum of conditions, which include manifestations arising from post-zygotic somatic mosaic anomalies, such as hemimegaloencephaly, lateralized overgrowth, and isolated macrodactyly (1–4). These syndromes have historically been identified based on the consistent combination of symptoms present.

One exemplary illustration of this diagnostic approach is Proteus syndrome, which is characterized by progressive skeletal overgrowth with asymmetry, along with epidermal nevi and plantar cerebriform connective tissue nevi (5, 6). Similarly, Sotos syndrome is defined by symmetric overgrowth, distinctive dysmorphia including a long narrow face, sparse frontotemporal hair, and an elongated pointed chin, along with doughy skin and frontal bossing (7). Though clinical diagnosis remains prevalent, advancements in the past two decades have unraveled/revealed the molecular underpinnings of these syndromes. For instance, Proteus syndrome arises from somatic activating mutations in the AKT1 gene, while Sotos syndrome results from inactivating mutations or copy number losses of the NSD1 gene. Molecular testing has not only verified diagnoses but also expanded the clinical phenotypes to encompass atypical cases, often with distinct molecular mechanisms (8, 9).

In addition to the intricate challenges posed by disproportional growth, which encompasses the potential for disfigurement, compromised mobility, and social seclusion, overgrowth syndromes carry an array of associated co-morbidities. Among these, the most profound, in terms of morbidity implications, is the heightened predisposition to cancer. The convergence of genetic etiologies in these syndromes towards growth signaling pathways provides a cogent explanation for the escalated vulnerability to neoplastic conditions. This hypothesis, initially proposed and subsequently substantiated, underscores the fact that affected children exhibit an elevated risk of malignancies (10, 11). This assertion is rooted in well-documented two-hit models, wherein the occurrence of genetic mutations in critical genes manifests as the cornerstone of tumorigenesis (12). Resultant tumors predominantly manifest as blastoma types, encompassing pleuropulmonary blastomas, hepatoblastomas, and nephroblastomas (Wilms tumor) (13–15). Furthermore, many of these syndromes are characterized by the presence of vascular malformations, hyperinsulinism, and developmental delays. We will focus on these as the four most common complications of overgrowth syndromes. The forthcoming discussion will offer a succinct overview of the prevailing overgrowth syndromes, concentrating on recent breakthroughs and observations. These syndromes will be categorized initially based on their symmetry, subsequently by their specific growth signaling pathways, and ultimately by the prevalence of four common co-morbidities.

It is within the ambit of this all-encompassing review to prioritize two cardinal themes: (1) the strategic approach to diagnosis in the context of children manifesting overgrowth syndromes, and (2) the most contemporary strategy for treatment and vigilant surveillance, contingent on molecular diagnoses. The fundamental objective guiding this endeavor is the standardization of the diagnostic pathway for these young patients, thereby expediting the diagnostic timeline, enabling rigorous monitoring, and delivering tailored therapeutic interventions.

Symmetry

One of the most distinct differentiations to be made when assessing a child with overgrowth pertains to determining whether the growth patterns manifest either symmetrically and ubiquitously or asymmetrically and in a mosaic manner (16). We are using the term “ubiquitous” as opposed to “germline” to clarify that these changes are expressed in most or all tissues in a patient leading to symmetric overgrowth. The classification of overgrowth syndromes can be broadly categorized based on these characteristics. When focusing on symmetry, various clinical tools can be harnessed. These include measurements of extremity circumference, palm, and foot length, as well as visual inspection. Radiologic examinations occasionally become necessary to elucidate more intricate findings, such as hemimegaloencephaly, which may initially appear as megalencephalic until a detailed visualization of the brain is achieved. Notably, these two clinical subgroups also mirror mechanistic distinctions: asymmetric/mosaic conditions typically arise from gain-of-function mutations, while symmetric/ubiquitous conditions tend to be precipitated by loss-of-function mutations. Despite the absence of rigid rules, exceptions like PTEN mosaicism are progressively emerging (13).

A comprehensive overview of the differentials between symmetric/ubiquitous and asymmetric/mosaic conditions is presented in Figure 1, constituting an initial and substantial step in the diagnostic approach. Beyond narrowing the potential etiologies, the tissue(s) affected and access to the tissues for testing is critical for the chosen testing approach and the underlying substrate. In mosaic conditions, the physician needs to be judicious in selecting the DNA to be sequenced and in interpreting the results. To illustrate, instances in which an isolated occurrence of hemimegaloencephaly or macrodactyly is observed may yield negative results when DNA is isolated from the cellular composition of white blood cells, since the cells precipitating the phenotype are often secluded from the lineages of white blood cells. In such scenarios, direct tissue sampling through biopsy or tissue collection during surgical procedures proves preferable, as evidenced by lymphatic disorders attributed to KRAS mutations (17). Furthermore, when blood variant frequencies are juxtaposed with frequencies in tumors, insights into diagnostic and therapeutic implications can be gained (18). As an emerging avenue, preliminary data suggests that cell-free DNA extracted from cerebrospinal fluid could serve as an alternative for patients displaying isolated CNS mosaicism where surgical intervention is not needed; however, the suitability of this approach necessitates further validation through large-scale studies (19). In addition to considerations of the substrate, the depth of analysis assumes paramount significance, since allele frequencies, even within affected tissues, can often be quite low. Consequently, panels with increased read depth and detection rates below the 1% threshold are highly recommended.

Figure 1:

Differential diagnosis for symmetric/ubiquitous and asymmetric/mosaic overgrowth conditions. Created with BioRender.com.

Growth Signaling Pathways

Genes responsible for overgrowth syndromes tend to cluster within growth signaling pathways, and a prominent example of this phenomenon is the PI3K-AKT-mTOR pathway (20). Mutations occur at various levels of this pathway, leading to distinct overgrowth phenotypes. These mutations encompass loss-of-function alterations in negative regulators like PTEN and TSC, as well as gain-of-function changes in pathway activators such as PIK3CA, AKT, and mTOR. This genetic variability results in distinct syndromes. For instance, Proteus syndrome is linked to somatic mutations in AKT1. The PIK3CA-related overgrowth spectrum comprises several syndromes (CLOVES syndrome, Megalencephaly-capillary malformation syndrome, Fibroadipose hyperplasia, Hemihyperplasia-multiple lipomatosis syndrome, and Klippel-Trenaunay syndrome) all characterized by somatic mutations in PIK3CA. Another example is PTEN hamartoma tumor syndrome, encompassing Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and autism-macrocephaly, resulting from mutations in PTEN. Additionally, tuberous sclerosis is caused by mutations in TSC1 and TSC2 genes. These genetic variations significantly contribute to the development and manifestation of these syndromes within the pathway. The identification of this pathway and its implications in cancer formation has led to the development of pharmacologic agents which are actively being studied and applied to the treatment of overgrowth syndromes and their complications (21–24).

Another significant category of disorders revolves around genes responsible for epigenetic regulation and maintenance, rather than the disruption of a single signaling pathway. This group encompasses various syndromes, each with distinct genetic mutations contributing to their manifestations. For instance, Sotos syndrome is associated with mutations or deletions in NSD1, responsible for encoding a histone methyltransferase (25). Weaver syndrome is characterized by variants in EZH2, which has histone methyltransferase activity. Variants in DNMT3A, a DNA methyltransferase, lead to Tatton-Brown-Rahman syndrome. Malan syndrome results from variants in NFIX, a pivotal transcription factor in epigenetic regulation. Imagawa-Matsumoto syndrome involves SUZ12, a component of the PRC2 complex, which facilitates the addition of methyl groups to histone proteins. SUZ12 collaborates with core PRC2 components EZH2, EED, and RBAP48 to catalyze methylation at lysine 27 on histone H3 (H3K27), resulting in H3K27 methylation modification (26). Notably, Beckwith-Wiedemann syndrome sheds light on the connection between epigenetic dysregulation and growth disorders. This syndrome demonstrates specific imprinted region dysregulation on 11p15, influencing the expression of H19, IGF2 and CDKN1C. While more research is necessary to comprehend the precise implications of other mutations within this category, global methylation appears intricately tied to the regulation of growth processes (27).

The remaining overgrowth syndromes do not cluster as linearly; however, they do highlight some important biological processes. For example, the DICER1 syndrome and GLOW syndrome implicate microRNA regulation in growth regulation and Simpson-Golabi-Behmel syndrome ties GPC3 into controlling human linear growth through an unknown mechanism (8, 28).

Comorbidities

> Cancer Predisposition

A number of overgrowth syndromes include an increased predisposition for specific tumor types, highlighting the need for accurate clinical and molecular diagnosis. To ascertain these risks, extensive investigations and large-scale studies are indispensable. Tumor screening recommendations vary based on syndrome, but several overall guidelines have been developed based on tumor type (29–31). The timing of symptom onset, a crucial factor, delineates the framework within which these screening recommendations are crafted, accounting for age-related susceptibilities and developmental nuances.

Certain syndromes, backed by robust clinical evidence, stand out for their well-documented association with specific tumor predisposition. Beckwith-Wiedemann syndrome (BWS) is intricately linked to the heightened likelihood of developing Wilms tumor, hepatoblastoma, and adrenal cortical carcinoma, setting this syndrome apart from the others above as exhibiting a higher risk profile (32). PTEN hamartoma tumor syndrome (thyroid, endometrial, and breast cancer) has guidelines (29–31, 33). Other syndromes are linked to different tumor types, but screening recommendations are not formalized such as Sotos syndrome (neuroblastoma, leukemia, and brain tumors) (29, 33).

It is of paramount significance to emphasize that the presence of isolated case reports detailing the occurrence of tumors within these syndromes does not in and of itself substantiate a definitive pattern of cancer risk (34–36). This realization underscores the imperative of conducting in-depth investigations encompassing extensive cohort studies and meticulous meta-analyses to precisely quantify these risks. Such endeavors become even more crucial in light of the multifaceted nature of these syndromes, necessitating a nuanced understanding that goes beyond the confines of individual cases. This ongoing documentation of malignancies within these syndromes forms a foundational basis for accurate risk assessments and underlines the essential role that collective clinical data play in shaping our understanding of these complex interactions.

A compelling illustration of this emerging understanding can be found in the context of Tatton-Brown-Rahman syndrome, where an evolving risk of hematopoietic malignancies has been reported. Recent case reports highlight the occurrence of various hematopoietic malignancies within this syndrome, revealing a potential risk profile, particularly for acute myeloid leukemia (AML) (37). Extrapolating from this data, an estimated risk of roughly 2% emerges within the Tatton-Brown-Rahman syndrome population. Notably, this calculation draws from the cumulative experiences of the Tatton-Brown-Rahman syndrome community to reach a denominator, emphasizing the necessity of age-adjusted and developmentally sensitive screening considerations.

The intricate nature of these considerations further underscores the significance of engaging in dedicated forums for interdisciplinary discourse. These discussions should find their platform in national consensus guidelines, with the American Association for Cancer Research (AACR) serving as a prominent example (38). In these forums, a confluence of oncology, genetic, and research expertise can foster the formulation of comprehensive strategies that holistically address the intricate balance between risk and intervention.

> Vascular Malformations

Certain overgrowth syndromes are recognized for their correlation with vascular malformations, underscoring the complex nature of these conditions. With few exceptions these syndromes cluster in the PI3K signaling pathway and furthermore present with a mosaic distribution. Outside of these syndromes, recent work has shown a role for activating mutations in KRAS and their responsiveness to certain pharmacologic inhibitors. Since these conditions have not been reported to occur with overgrowth, they will be omitted from this review (17).

The overgrowth syndromes most commonly associated with vascular malformation include Proteus syndrome, CLOVES, megalencephaly capillary malformation syndrome, Klippel-Trenaunay syndrome, Sturge-Weber syndrome, Schaaf-Yang syndrome, Cantú syndrome, and the PTEN hamartoma tumor syndrome.

> Developmental delays

In the domain of overgrowth syndromes, a subgroup of conditions presents with a range of developmental delays. An illustrative example is Sotos syndrome, which includes developmental delays often encompassing speech and motor skills. This phenomenon underscores a significant connection between growth signaling, brain development, and the trajectory of normal growth. This relationship has been a long-standing observation within the context of autism, where multiple reports have affirmed the correlation between autism, macrocephaly, and, in certain instances, mutations in the PTEN gene (39).

Similarly, Weaver syndrome portrays an image of excessive growth alongside notable delays in both motor and speech domains. Malan syndrome includes developmental delays, intellectual disabilities, and speech impediments. Tatton-Brown-Rahman syndrome, with its distinct characteristics, frequently depicts developmental delays and intellectual disabilities. Concurrently, Bannayan-Riley-Ruvalcaba syndrome (BRRS) and Luscan Lumish syndrome include developmental delays and challenges in learning. Cohen syndrome includes developmental delays, intellectual disabilities, and complexities in social interaction.

> Hyperinsulinism

The last complication that we will highlight is hyperinsulinism, which occurs in several overgrowth syndromes. The mechanism for this condition broadly divides into stress hyperinsulinism and congenital hyperinsulinism, where congenital hyperinsulinism has been studied and is known to result from specific mutations within the potassium channel of the B-cell which leads to itsconstituitive activation. There are also two primary overgrowth syndromes that can feature hyperinsulinism, Beckwith-Wiedemann syndrome and Sotos syndrome (40, 41). Similarly, hyperinsulinism has been reported in both Weaver syndrome and PIK3CA-related overgrowth spectrum (42). This finding has led to the inclusion of these genes (NSD1 and NFIX) on hyperinsulinism panels which sometimes leads to the identification of underlying overgrowth syndromes in these cases with hyperinsulinism as the presenting symptom.

Diagnostic Algorithm

Based on the aforementioned recommendations and observations, we have devised a diagnostic algorithm tailored to pediatric cases involving overgrowth (Figure 2). This framework aims to establish a standardized approach for addressing these cases and to facilitate the administration of timely and appropriate assessments and care. Our primary objective is the early identification of individuals exhibiting overgrowth, with emphasis on height, weight, and/or head circumference measurements deviating by three standard deviations from the mean or surpassing the 99th percentile, in relation to age and gender-matched peers.

Figure 2:

Diagnostic algorithm and approach to the child with overgrowth, Created with BioRender.com.

In the initial stages of the clinical examination, a pivotal determinant revolves around evaluating the symmetry of the overgrowth. Our strategy capitalizes on the relatively narrow spectrum of conditions characterized by asymmetric overgrowth. This underscores the need to concentrate our diagnostic efforts on acquiring the requisite foundation for comprehensive testing. For patients presenting with asymmetrical overgrowth alongside vascular malformations, we advocate the consideration of tissue biopsy where feasible. The obtained tissue samples should then undergo in-depth sequencing, encompassing the PIK3CA gene, among other pertinent genes.

In our approach, we endorse the utilization of commercially available gene panels with an increased sensitivity for detecting mosaicism (43, 44). Supplementary resources within the documentation provide access to these testing facilities.

In instances where patients lack evident vascular malformations but manifest subtler forms of lateralized overgrowth, our attention turns towards the consideration of Beckwith-Wiedemann syndrome/spectrum. In the pursuit of this clinical diagnosis, we employ the Beckwith-Wiedemann spectrum clinical score (45). This scoring system can facilitate a clinical diagnosis, thus aiding in decision-making for the benefit of our patients.

In the context of symmetric overgrowth conditions, a notable subset encompasses cases exhibiting disproportionate macrocephaly. In these instances, an essential step involves the application of advanced brain imaging techniques to uncover underlying conditions, including hemimegaloencephaly, megalocephaly, and hydrocephalus. Currently, the diagnosis of these cases presents a complex challenge; however, promising advancements in testing strategies are steadily emerging to address this conundrum(19, 46).

Turning our attention to patients demonstrating symmetric overgrowth, a systematic evaluation is paramount to discern hallmark features associated with well-established overgrowth syndromes. Noteworthy examples encompass the presence of supernumerary nipples—a characteristic finding in Simpson-Golabi-Behmel syndrome, doughy skin manifestations observed in Sotos syndrome, and the identification of a freckled glans of the penis, which is indicative of PTEN hamartoma tumor syndrome. These distinctive clinical signs can serve as a catalyst for targeted gene panel testing. This testing regimen encompasses scrutiny of sequence variants and copy number variants at the exon level of resolution using gene panels. Within this category, the use of DNA isolated from peripheral blood often proves sufficient for arriving at an accurate diagnosis.

For cases categorized as undifferentiated overgrowth, where diagnostic clarity remains elusive, we advocate the implementation of comprehensive sequencing methodologies, notably whole exome or genome sequencing. As the landscape of genetic testing continues to evolve, novel technologies have emerged to detect methylation changes and characteristic signatures (47). While these innovative techniques show promise, it is important to underscore that their validation process is ongoing. Should massively parallel sequencing testing yield non-diagnostic outcomes, these emerging approaches, backed by rigorous validation, could potentially be considered to address the diagnostic challenges posed by undifferentiated overgrowth cases.

Screening Considerations

For a subset of overgrowth syndromes there are published and established screening recommendations. These include Beckwith-Wiedemann syndrome, Simpson-Golabi-Behmel syndrome and the PTEN hamartoma tumor syndrome (Current screening guidelines are outlined in Table 1).

Table 1.

Overgrowth syndromes with screening guidelines

Syndrome	Increased Risk of	Screening Recommendations
Beckwith-Wiedemann Syndrome (BWS)	Wilms tumor and Hepatoblastoma	- Tumor screening includes a full abdominal ultrasound every 3 months until age 4 years, and renal ultrasound from age 4–7. - Additionally, alpha-fetoprotein screening is recommended every 3 months until age 4 years to screen for development of hepatoblastoma. (Except for patients with CDKN1C mutations)
Simpson-Golabi-Behmel Syndrome (SGBS)	Wilms tumor and Hepatoblastoma	- Follow BWS guidelines for WT and HB risk
PTEN Hamartoma Syndrome	Thyroid, skin and colon cancer	- Yearly thyroid ultrasound starting at the time of first diagnosis - Yearly Skin Check

For the remaining overgrowth syndromes, there are emerging suggestions; however, no consensus statements regarding the use of tumor screening exist. We favor a one-time abdominal ultrasound, which can serve as a baseline examination as well as document organomegaly or renal differences. The ultimate plan for tumor screening in patients with overgrowth should be undertaken with joint decision-making with the parents, while following the most up-to-date consensus statements.

Treatments

Perhaps the most exciting avenue in the field of overgrowth syndromes is the testing of use of targeted therapies to address symptoms. As presented above, overgrowth syndromes encompass a group that can lead to a range of clinical manifestations, from benign overgrowths to complex clinical presentations. On the more severe end of this clinical spectrum lies the conditions associated with lymphatic and vascular malformations. The majority of advancements in the field have been aimed at the treatment of these vascular malformations with targeted inhibitors. Conditions with recent advancements are listed below (advancements from the past 18 months are summarized in Table 2).

Table 2.

Recent advancements to the treatment of overgrowth syndromes

Diagnosis	Symptom	Treatment	Side Effects	Outcome	N	Age*	Source
Central conducting lymphatic anomaly (CCLA)	Lymphatic Malformations	Trametinib (0.005g - 0.025 mg/kg daily)	One report of rhabdomyolysis (known side effect of trametinib)	Ongoing management	2	13	(17)
CLAPO syndrome	Capillary, lymphatic, and venous malformations	595-nm PDL irradiation	Transient bruising, with one case of post-inflammatory hypopigmentation	All lesions responded to treatment with clearance > 75% in 4/7 patients	7	13–58	(48)
CLOVES syndrome	Vascular Malformations	Sirolimus	None-life threatening; minor side effects included: neutropenia, lymphopenia, infection, and ulcer	93% reported improvement in QOL. 86% had improvement in one symptom. 89% had improvement in D-Dimer or Fibrinogen levels	30	0–42.36	(49–53)
		Alpelisib (50 mg/day)	None	Rapid, positive response. Reduction in overgrowth	1	2
Klippel Trenaunay syndrome (KTS)	Capillary lymphatic venous Malformation	Sirolimus	None were life-threatening. Minor side effects include: neutropenia, lymphopenia, infection, ulcer	93% reported improvement in QOL. 86% had improvement in one symptom. 89% had improvement in D-Dimer or Fibrinogen levels	29	0–42.36	(52, 54)
	Persistent Embryonic Lateral Marginal Vein of Servelle	Radiofrequency Ablation + Sclerotherapy with Polidocanol	None.	Immediate improvement with good cosmetic results. Resolution of lateral vein.	1	19
Malan syndrome	Anxiety & Self-Destructive Behavior	Mirtazipine	None reported	Symptoms resolved with treatment.	1	26 (avg.)	(55)
	Epilepsy	Valproic Acid, Topiramate		Mixed success with some patients reporting positive results. Consult your physician for individualized care	2	4
Sotos syndrome	Central Precocious Puberty	Leuprolide Acetate & Cyproterone Acetate	None.	Cyproterone Acetate was successful after Leuoprolide was discontinued. Testicular volume reduction and basal testosterone level suppression.	1	6.5 month	(56)
PIK3CA related overgrowth spectrum (PROS)	Hypertrophy	Sirolimus (po)	Infection, hematologic changes, liver toxicity	Reduced hypertrophy, significant reduction in volume	58	NR	(57–59)
	Growth Retardation	Growth hormone	No reported adverse effects	Well tolerated, growth recovery	NR	NR	(23)
	Overgrowth	Liposuction	None.	Size reduction with improved QOL	17	NR	(24, 58, 60, 61)
		Alpelisib (25–150 mg/day)	Significant side effects rare. Minor side effects include: gastrointestinal inflammation or ulcer, hyperglycemia,	Reduction in overgrowth, relieved pain, improved QOL. Improvements in swelling, swallowing, and coloration. Valuable between overgrowth surgeries. Functional improvement.	21	26 (avg)
		Miransertib	Off-label use, hyperglycemia	Reduction in soft tissue volume	NR	NR	(58)
	Solid Tumors	PIK3 Inhibators (e.g., Buparlisib, copanlisib, Alpelisib, taselisib, Everolimus, capivasertib, ipatasertib)	Variety of minor and major adverse effects	Multiple therapies have demonstrated promising preliminary results	NR	NR	(21)
	Vascular Malformations	Sirolimus & Alpelisib (50 mg/day)	Mouth sores	Analgesia, patient able to return to athletic participation. Visible reduction in symptoms and improvement in QOL and range of motion	3	6–12	(60, 62, 63)

Central conducting lymphatic anomaly (CCLA) is associated with lymphatic malformations and is diagnosed based on clinical evaluation. Trametinib has been employed as a treatment. However, it is noteworthy that one report documented a case of rhabdomyolysis as a side effect of trametinib. Patients with CCLA require ongoing management to achieve optimal outcomes (17).

CLAPO syndrome is characterized by capillary, lymphatic, and venous malformations. Treatment involves 595-nm Pulsed Dye Laser PDL irradiation, which has proven effective in clearing lesions by more than 75% in 4 out of 7 patients. Although transient bruising is a common side effect, post-inflammatory hypopigmentation was reported in a single case(48).

CLOVES syndrome presents with overgrowth of various tissues and is treated using sirolimus and alpelisib. While the side effects are generally non-life-threatening, they may include neutropenia, lymphopenia, infection, and ulcer formation. However, an impressive 93% of patients have reported improvements in their quality of life, with reductions in overgrowth and improved biomarker levels (49–53).

Klippel Trenaunay syndrome (KTS) is characterized by capillary lymphatic venous malformation and a persistent embryonic lateral marginal vein of Servelle. Treatment options include sirolimus and radiofrequency ablation combined with sclerotherapy using polidocanol. Minor side effects include neutropenia, lymphopenia, infection, and ulcer formation. Patients with KTS have reported immediate improvements with good cosmetic results, including the resolution of lateral veins (52, 54).

PIK3CA-related overgrowth syndrome is characterized by excessive tissue growth, solid tumors, and vascular malformations. Treatment options include sirolimus, alpelisib, and other PIK3 inhibitors, with varying side effects such as infection, hematologic changes, and liver toxicity. However, these therapies have demonstrated promising preliminary results in reducing overgrowth and improving quality of life. They are often used between overgrowth surgeries (60, 62, 63).

Outside of vascular and lymphatic malformations, interventions have been more individualized and so far, have no unifying mechanism. Such is the case with Malan syndrome, which is associated with anxiety, self-destructive behavior, and epilepsy. Treatment strategies include mirtazipine and valproic acid or topiramate. Fortunately, no side effects have been reported, and symptoms tend to resolve with treatment. While some patients have reported mixed success, individualized care with close physician supervision is recommended (55). Additionally, Sotos syndrome can lead to central precocious puberty for which management with leuprolide acetate and cyproterone acetate is recommended. Notably, cyproterone acetate has shown success after leuprolide was discontinued, resulting in testicular volume reduction and basal testosterone level suppression (56).

A major frontier that is yet to be explored is the role of targeted inhibition on the comorbidities of overgrowth syndromes. Careful studies and considerations are necessary to weigh the risks and benefits for novel therapies, also larger sample sizes are needed to establish the usefulness and effectiveness of these treatments.

Conclusion

Overgrowth syndromes encompass a spectrum of disorders, each requiring tailored approaches to diagnosis and treatment. The management of these conditions has evolved with a focus on improving quality of life and minimizing side effects. Research and clinical experiences continue to shape the treatment landscape for individuals affected by these syndromes, offering hope for a brighter future for patients and their families. Close collaboration between healthcare professionals and patients is crucial in achieving the best possible outcomes.

Summary Points.

• The systematic approach to the child with overgrowth will aide in timely clinical diagnosis and selection of the appropriate molecular testing.

• Diagnosing the specific overgrowth syndrome allows appropriate clinical management including tumor screening when needed and therapeutic interventions when available.

• The most common features of overgrowth syndromes include vascular malformations, cancer predisposition, and developmental delays.

• Many genes responsible for human overgrowth cluster within the PI3K-AKT-mTOR pathway, and in regulators of global epigenetic maintenance.