Noonan syndrome (NS, OMIM PS163950) is one of the most common non-chromosomal disorders affecting development and growth (1). It is largely transmitted as a dominant trait, even though two recessive forms have recently been identified (2, 3). NS was first described by the cardiologist Jaqueline Noonan in 1968 (4), who reported a previously unrecognized phenotype with pulmonary valve stenosis (PVS), short stature, variable cognitive deficits, and facial dysmorphism as recurrent major features. NS is a syndromic condition characterized by a distinctive facial gestalt (e.g., relative macrocephaly, hypertelorism, ptosis, and low-set/posteriorly rotated ears), failure to thrive in the first years of life, reduced postnatal growth, a wide spectrum of congenital and acquired cardiac defects (most commonly PVS and hypertrophic cardiomyopathy [HCM)]), varying degrees of developmental delay (DD)/intellectual disability (ID), typical chest deformities (superior pectus carinatum, inferior pectus excavatum), tendency to bleed and cryptorchidism in males (5–7).

The variable clinical phenotype of NS overlaps with those of other genetic syndromes originally categorized as NS-spectrum disorders (NSSD) ( Figure 1 ). Among these, NS with multiple lentigines (NSML, previously known as LEOPARD syndrome; OMIM 151100), Mazzanti syndrome (also known as NS-like disorder with loose anagen hair) (NS-LAH; OMIM 607721 and 617506), Legius syndrome (LGSS; OMIM 611431), and a phenotype originally denominated neurofibromatosis-NS (OMIM 601321), a condition representing a distinct form of neurofibromatosis 1 (NF1, OMIM 162200) are the most closely related conditions. There are also significant clinical overlaps with cardiofaciocutaneous syndrome (CFCS; OMIM 115150), and Costello syndrome (CS; OMIM 218040) (8–10), and other recently recognized diseases (11, 12). Unsurprisingly, the molecular mechanisms underlying the pathogenesis of these disorders are closely related. These disorders are caused by germline mutations in genes encoding components of the RAS-mitogen-activated protein kinase (MAPK) pathway, a signal transduction cascade controlling key cellular processes (e.g., proliferation, differentiation, migration and metabolism) in response to a wide array of growth factors, hormones and cytokines ( Figure 1 ) (13). Because of these shared mechanisms, these disorders are collectively termed as RASopathies (7–10). Multiple key players in this pathway are mutated in NSSD, with an overall gain-of-function effect on signal flow through the RAS-MAPK pathway (9).

The wide clinical variability characterizing NS results from a particularly marked genetic heterogeneity. Heterozygous germline mutations in 12 genes have been reported to be associated with NS (PTPN11, SOS1, SOS2, KRAS, NRAS, RIT1, MRAS, RAF1, BRAF, MAP2K1, LZTR1, and RRAS2) (1, 6, 8, 10, 14). Moreover, at least two genes have been reported as causing recessive forms of NS (LZTR1 and SPRED2) (2, 3). Mutations in the PTPN11 gene account for approximately 50% of NS cases, and mutations in LZTR1, RIT1, SOS1 and RAF1 for the majority of the remaining cases (1, 6–8, 10). Genetic mutations have not been identified in a small proportion of subjects with a clinical diagnosis of NS, supporting the existence of additional genes implicated in the disorder (14). Most NSSD causative pathogenic variants act through a gain of function mechanism on the RAS/MAPK signaling cascade that destabilizes the autoinhibitory mechanisms that maintain these proteins in their catalytically inactive conformation. Inactivating pathogenic variants affecting regulatory proteins that negatively control the RAS/MAPK cascade may also cause NSSD, and may act as either loss-of-function (LoF) (e.g., SPRED1, SPRED2, neurofibromin and LZTR1 in the recessive form of NS) or dominant-negative (DN) (LZTR1 in the dominant form of NS) mutations (3, 11, 15, 16).

From an auxological point of view, NS is one of the most prevalent non-chromosomal disorders affecting development and growth (17, 18). In affected subjects, birth weight and length are generally normal, although postnatal growth failure is observed (19, 20). Commonly, height tends to follow the third centile from ages two to four years until puberty, when below-average height velocity and an attenuated pubertal growth spurt tend to occur with a near adult height in the lower limits of normal values (21–23).

In NS, decreased insulin-like growth factor I (IGF-I) and IGF binding protein 3 (IGFBP-3), together with low responses to GH pharmacological provocation tests (GHST), may suggest, for some patients, an impaired growth hormone (GH) release or disturbance of the GH/IGF-I axis. Variable GH resistance, particularly in subjects with PTPN11 pathogenic variants, has also been reported (21). Short stature may be in part related to other factors (24, 25), such as congenital heart disease (CHD) requiring surgery (25); in fact, cardiac involvement is a main clinical feature (70-80%) of NS and cardiac anomalies are mostly represented by congenital heart diseases (in particular PVS) and HCM (20%) (25). Nearly 50% of NS patients present with some electrocardiographic abnormalities, even in the absence of structural cardiac abnormalities (25).

Emerging evidence shows that the molecular cause underlying the disease has a specific impact on stature, as demonstrated by a more severely impaired growth in patients carrying PTPN11, RAF1, and KRAS pathogenic variants compared to those with SOS1 variants (24).

Although neurocutaneous manifestations have been considered hallmark features in NS and other RASopathies, other organs and systems, including the musculoskeletal system, may be affected (26). Musculoskeletal anomalies include scoliosis, kyphosis, anterior chest wall anomalies, pes planus, osteopenia, and hand anomalies (26, 27). The central nervous system may also be affected by congenital malformations; a few cases of Arnold-Chiari I malformation have been described, though the true incidence in NS is not known (28, 29).

Finally, NS is associated with a higher risk for benign and malignant proliferative disorders, such as juvenile myelomonocytic leukemia (JMML) and/or other hematological malignancies, as well as solid tumors, specifically neuroblastoma, solid brain tumors, and embryonal rhabdomyosarcoma (30–33).

NS diagnostic criteria were originally published by van der Burgt in 2007 (34). They are of particular value in research, and they were the basis for the more recently developed guidelines by Dyscerne (35), which set out recommended baseline investigations and age-specific management of patients. Similar recommendations are provided by Romano et al. (36), Roberts et al. (1) and, after GH treatment approvals in Europe, by Carcavilla et al. (8).

After 2007, when the Food and Drug Administration (FDA) approved recombinant human GH (rhGH) treatment for short stature in NS, the treatment was subsequently approved in Brazil, Israel, Japan, South Korea, Switzerland and some European countries (8, 17). For this reason, many studies conducted in the past evaluating the response and safety of rhGH treatment in NS patients were performed in subjects with concomitant GH deficiency (GHD) who were therefore treated with standard doses for this diagnosis. To date, most studies on rhGH treatment for NS have been retrospective and observational, involving small numbers of patients, with variable ages at the start of treatment and treated with different doses. Unfortunately, molecular characterization is available for only a small number of these cohorts (8, 17).

Here, we review and critically assess data from the literature on the growth pattern characterizing NS, altered GH/IGF-1 axis, and efficacy and safety of rhGH treatment in NS. PubMed and Google scholar tools were used to retrieve relevant publications by using the following terms: Noonan syndrome, PTPN11, KRAS, SOS1, RAF1, NRAS, BRAF, MEK1, RIT1, SOS2, LZTR1, MRAS, CBL, RRAS, RRAS2, RASA2, SPRED1, growth, growth hormone, GH, GH treatment, puberty, scoliosis, cancer, tumor, brain tumor, MRI, Chiari malformation, dysembryoplastic, pilocytic, medulloblastoma, oligodendroglioma, glioneuronal, astrocytoma, glioma, ependymoma,pulmonary stenosis, and hypertrophic cardiopathy. We included reviews, case reports, case series and case report abstracts.

Up to 70% of NS subjects present with postnatal short stature (17, 37), even though the majority has a normal birth weight and length (20); the presence of edema may result in an overestimation of weight which should be carefully evaluated (20). Some authors have reported a significantly higher frequency of NS subjects who are small for gestational age (SGA) compared with the general population (24%), particularly for length (24), and in specific genotypes (24, 38). Attention should be paid to SGA patients whose phenotypic characteristics are suggestive of a RASopathy, and to children who do not respond to GH treatment (39). The concomitant diagnosis of SGA and NS may affect the responsiveness of a child to the growth-promoting effects of rhGH treatment (39). Prematurity has also been reported in a significant proportion of patients and should be taken into account when evaluating NS individuals (24, 40).

Feeding difficulties in NS subjects are extremely frequent (19) and may cause transient failure to thrive and poor weight gain during the neonatal period and infancy in 55 to 100% of cases, depending on the molecular subtype (20, 41).

Birth length is, however, usually normal, although postnatal growth failure is commonly observed starting during the first years of life (20); in fact, mean height tends to follow the third centile from ages two to four years until puberty, when below-average height velocity and an attenuated pubertal growth spurt tend to occur (20).

As bone age is usually delayed, prolonged growth into the 20s may occur, attenuating the growth deficit in some subjects (20). Near adult height approaches the lower limits of normal values: 161-167 cm in males and 150-155 cm in females, with a -1.5 SDS compared to the normal population (20, 21). On the contrary, more than 50% of females and nearly 40% of males have an adult height below the third centile (22).

Growth charts, not genotype-specific, have been developed, although evidence for the occurrence of short stature is represented by pooled data expressed in standard deviation scores (SDS) from patients at different ages, thus precluding a longitudinal description of growth (20–22). Currently available NS-specific growth charts should be used with caution, as they are not genotype-specific and often refer to patients for whom the clinical diagnosis had not been molecularly confirmed.

As reported, in patients with NSSD, the underlying molecular cause of the disease has a specific impact on stature (24). In fact, growth retardation appears to be significantly less severe and less frequent in patients with NSML and NS associated with SOS1 mutations compared to patients with NSSD associated with pathogenic variants in other RASopathy genes, such as patients with PTPN11, RAF1, and KRAS mutations (24).

NS individuals generally present with a normal BMI during the first years of life (24, 42), followed by relative ‘thinness’ with a BMI in the lower normal range; it is rare for NS patients to be overweight or obese, suggesting that NS-causing mutations could impact energy metabolism regulation (36, 43, 44). The greatest decrease in BMI has been associated with pathogenic SHOC2, KRAS and HRAS variants, occurring in NS-LAH, CFCS and CS. These patients present with marked failure to thrive substantially due to muscle tissue wasting rather a decrease in adipose tissue (44). A possible correlation between metabolism and control of energy storage has been hypothesized (45, 46), which may involve two important hormones involved in unsatiety signals (insulin and leptin) and the RAS/MAPK pathway. As proof, patients with CS display an increased resting energy expenditure and a high calorie intake compared with the recommended levels of energy intake (47).

There may be other metabolic alterations in RASopathies. In the NSML mouse model, reduced fat mass and resistance to diet-induced obesity with increased carbohydrate metabolism/insulin sensitivity has been reported (48). On the other hand, the NS mouse model shows an insulin resistant phenotype associated with inflammation of tissues involved in the regulation of glucose metabolism likely due to increased activation of macrophage and triggered monocyte infiltration through SHP2 induced RAS/MAPK hyperactivation (49).

Puberty is often delayed in NS subjects (5), in both females (22%) and males (34%) (50). Those with delayed puberty, frequently resembling a constitutional delay of growth and puberty, are usually shorter and thinner than NS individuals with normal puberty (50). Unfortunately, the molecular available data do not allow us to make accurate genotype-phenotype correlations (50).

As NS is a condition characterized by clinical variability and genetic heterogeneity, different mechanisms implicated with altered GH secretory dynamics or response have been reported, including GHD, neurosecretory dysfunction, and GH insensitivity (GHI) (17, 21). Decreases in IGF-I and IGF-binding protein 3, together with low responses to provocation tests, suggest impaired GH release, or disturbance of the GH/IGF-I axis, at least in a proportion of affected individuals (21).

Recent data suggest that germline activating BRAF mutations may lead to an abnormal differentiation of pituitary hormone-producing cells in the progenitors of the pituitary gland with postnatal hypopituitarism, suggesting a biological role of the MAPK pathway in the etiology of pituitary hormone deficiencies, and a biological link between congenital forms of human hypopituitarism and RASopathies (51). Data on hypopituitarism in NS are poor (52) and there remain many questions about the presence of GHD in subjects with NS.

In NS with growth impairment, the results of provocatory tests should also be taken into account as data indicate that approximately 40% of NS subjects have a GH peak below 10 ng/mL after GHST (53, 54) and some individuals may also present with a range of disturbances in GH secretion, such as low levels of mean overnight GH concentration and unusual GH pulsatility with high trough GH concentration, indicating a concurrent presence of a neurosecretory dysfunction (55). On the other hand, a recent paper studying 24hGH profiles in patients with NS or Turner syndrome (TS), and unaffected prepubertal children showed that GH-baseline, GH mean values, GHmax and other parameters were significantly higher in NS patients, particularly in those with PTPN11 variants, compared to healthy children (56). In fact, a mild GHI, related to a post-receptor signaling defect due to upregulation of SHP2, the protein encoded by PTPN11, has been reported in NS individuals with pathogenic PTPN11 variants (21). SHP2 acts as a negative regulator of the GH receptor signaling pathway and its anomalous activation could be partially compensated via a more elevated GH secretion, as occasionally observed in NS subjects treated with rhGH who showed a mild resistance to rhGH treatment (21). NS individuals carrying PTPN11 variants also have lower levels of insulin-like growth factor1 (IGF-1) than those without a PTPN11 variant (37) although it is not completely clear whether this ​​ indicates GHD or GHI in these individuals. We believe that it is important to assess whether sensitivity to GH is normal or decreased before introducing rhGH treatment (57). In a short and/or slowly growing NS child, serum IGF-I levels could be useful in distinguishing between GHD or GHI (57). If serum IGF-I is low (or in the lower half of the reference range) for age, sex, and pubertal stage, or height velocity is reduced, assessment of the endogenous GH reserve by GHST could be informative (58). “Classical” GHD can be excluded in the presence of a normal stimulated GH peak (57). If a diagnosis of GHD is established, we suggest that magnetic resonance imaging (MRI) of the hypothalamic/pituitary region is also carried out (58).

After 2007, when the use of rhGH received approval for treatment of short stature in NS by FDA, many countries (e.g., Brazil, Israel, Japan, South Korea, and some European countries), began to treat NS patients (59–64). In addition to cases treated for documented GHD, rhGH treatment has also been initiated in NS individuals in the presence of markedly short stature, defective function of the GH-IGF-I axis, and/or a documented response to rhGH treatment (59–62). No standard dose has been established, however, based on available data from Phase III clinical trials (65, 66), another long-term interventional study (61) and long-term real world data from the NordiNET IOS and ANSWER international registries (67), the recommended dose is 0.066 mg/kg/day (0.46 mg/kg/week); however, we suggest an initial dose regimen of 0.033 mg/kg/day which may be increased up to 0.066 mg/kg/day in cases of poor response, as reported on the medication label and also stated by other authors (8).

Unfortunately, it is difficult to systematically compare published data on rhGH treatment in NS due to heterogeneous protocols, potential enrolment bias, the small size of the cohorts studied, different cohort selection criteria and varying durations of therapy ( Table 1 ) (18, 54, 85). Most data on response to rhGH treatment derive from uncontrolled observational studies, frequently involving small numbers of patients, with different ages at onset of therapy, different rhGH doses, and varying durations of treatment (18). Noticeably, most individuals treated with rhGH were not genetically characterized, which is a drawback due to the marked clinical variability characterizing the disorder and reported genotype-phenotype correlations.

Short and long term studies have demonstrated a consistent and significant increase in HV in NS children and adolescents treated with rhGH (57, 59–61, 67, 86). Increases in height SDS vary from 0.6 to 1.8 and may depend on age at start of treatment and duration of treatment, age at onset of puberty and/or GH sensitivity (59, 60, 86).

Many retrospective, observational studies on rhGH treatment in NS patients with and without GHD as well as clinical trials in NS patients with short stature have been carried out over the past 20 years (42, 54, 59, 60, 64, 68–72, 74, 75, 78–80, 83). In some studies, auxological and safety data were consequent to rhGH dosages established on the whole cohort of NS patients with no distinction being made between subjects with GHD and subjects without GHD, while other studies included only NS subjects with GHD (54, 59, 60, 64, 69, 72, 75, 78–80, 83). In other studies, doses of rhGH varied according to different parameters, for example the pubertal stage of patients (21, 61, 66, 76, 81). International Registers (e.g., the Kabi International Growth Study [KIGS] database or the US National Cooperative Growth Study [NCGS]), report data for NS cohorts with and without GHD who were treated with rhGH with different dosages (62, 63, 67, 73, 77, 82).

Some short-term studies have demonstrated an increase in HV and an increase in mean height SDS (63, 68, 70, 71, 74), particularly in the first year of treatment (63, 68, 70, 71, 74), suggesting that short-term use of rhGH for managing short stature is effective in NS. In a study involving 30 patients with a clinical diagnosis of NS without genetic characterization, nearly 80% of patients (aged from 4.5 to 14.0 years and treated with 0.045 mg/kg/day of rhGH for 1 year) showed a significant increase in mean height SDS (-3.01 ± 0.1 to -2.36 ± 0.1) and HV (4.9 ± 0.2 to 8.1 ± 0.4 cm/yr) (70), highlighting the effectiveness of rhGH treatment in both prepubertal and pubertal patients (70, 76, 78). However, other studies indicate that high HV typically and gradually decreases every year after the first year of treatment (74, 78) despite adherence to therapy (63, 74). This waning effect is likely to be due to many co-occurring factors, such as age at the beginning of therapy, GH secretory status, and variable GHI. Indeed, a recent randomized, double-blind, multi-center trial investigating the effect of dose on the growth-promoting effect of rhGH in prepubertal children with NS demonstrated a significant increase in height gain with a dose of 0.066 versus 0.033 mg/kg/day (66). In addition to dose, factors associated with improved outcome include earlier initiation of rhGH therapy and longer prepubertal duration of therapy (61, 62, 82). The presence of genetic heterogeneity in NS also raises the possibility that different responses to rhGH treatment may be genotype-related (78). Unfortunately, genetic data are lacking in the majority of papers. Some data show that prepubertal NS children with GHD present an increased growth rate during rhGH treatment at a rate equivalent to girls with Turner syndrome but at a lower rate than in idiopathic GHD (63, 64). Nonetheless, these studies used very different rhGH dosages (63, 64).

Long-term data on the effect of rhGH treatment on height outcomes are poor and limited to a small number of patients. Data on adult height (AH) or near-adult height (NAH) in NS patients treated with rhGH are also available (42, 54, 61–63, 76, 77, 82, 87, 88), but refer to small cohorts whose results may be biased because of a number of factors, such as age at start of treatment, duration of treatment, and definitions of NAH (60–62, 81, 82).

Patients who were treated with rhGH for more than 3 years (median, 6.4 years) showed an increase in height of 1.3 SDS (26), with the majority of patients achieving an AH within the normal range and 30% remaining below -2 SDS (37, 84). Again, these differences might be due to several confounding factors (37), as well as the dose of rhGH (84). After one year of rhGH treatment, the mean difference between chronological age and bone age decreased (68), and this was particularly evident in subjects having a significantly delayed bone age at the start of rhGH therapy (62), reflecting a normalization rather than excessive acceleration of bone development in these individuals (37).

The bone age of rhGH-treated NS individuals with a significant increase in AH did not excessively advance during rhGH treatment (60, 74). Some data also show that, after rhGH treatment, most NS patients present with significant gains in AH, despite the pubertal growth spurt occurring much later than normal (37).

However, the possible relationship between a “reduced” advancement in bone age with later pubertal development and the effect on final stature is not clear.

Some studies report a more significant increment in height SDS after one to three years of rhGH treatment in patients without PTPN11 mutations (75, 76, 87). However, other data do not confirm these findings (78).

There are contrasting data about the influence of pre-treatment values of IGF-1 and IGFBP-3 on the effectiveness of rhGH treatment. While some studies suggest that basal IGF-I and IGFBP-3 levels before rhGH treatment are significantly related to final response (60), other data indicate that these levels cannot predict changes in height SDS (63, 67). Other studies reported significantly lower IGF-1 and IGFBP-3 levels at the start of rhGH therapy in some NS individuals carrying PTPN11 mutations (37). The choice of reference population is important when interpreting the magnitude of rhGH response. This is clearly illustrated by the differences in mean adjusted ΔHSDS at 5 years (national reference, 1.17, Ranke 1.46), though a similar effectiveness of treatment was observed irrespective of the reference used (88).

In summary, the available data confirm that rhGH treatment is associated with an increase in HSDS in NS individuals during childhood with a final increase in AH. It seems that the earlier rhGH treatment is started, the more likely an optimal height is reached due to height normalization and the delayed pubertal onset frequently observed in NS subjects. However, the scarcity of data on genetically characterized cohorts does not allow us to accurately determine whether response to rhGH treatment also depends on genotype.

Tables 2 and ( 3A , 3B and 3C ) show the results of the major studies on rhGH therapy in NS. Side effects in children were infrequently reported. Based on the data, rhGH treatment does not seem to influence cardiac physiology and function (38). The decision to use rhGH in patients with NS should, however, be made on a case-by-case basis (8). The accumulated safety data on rhGH treatment in NS are reassuring (60) and include no significant evidence of adverse cardiac effects or increased occurrence of malignancies (60–62).

We review some of the major concerns and side effects during rhGH treatment in NS individuals.

NS is a highly heterogeneous disorder, with variable clinical features and genetic complexity (1, 6–8, 13, 14), which must be taken into consideration when evaluating rhGH treatment in these patients. In addition to auxological and safety data, genetic data, often lacking, is essential for identifying patients at risk for specific side effects and complications during rhGH treatment. In many papers, diagnosis of NS is based only on clinical assessment (75), which makes it difficult to analyze the results and side effects for specific genotypes.

The presence of varying degrees of GHI in subjects with NS should not prevent clinicians from evaluating rhGH treatment, which should be individualized. Given the emerging data about neoplasms in NS patients, we recommend a conservative approach and judicious surveillance (8).

As in the general population, it is important to rule out GHD. The correct starting standard dose of rhGH has not been established in NS and high doses of rhGH are not recommended (175). In non-NS patients, some data suggest an increased risk for cardiovascular events (176) and increased incidence of secondary tumors (177) in children with a primary tumor who had been treated with rhGH during childhood and adolescence. Other authors have not found a significant increase in overall mortality in low-risk patients, such as those with isolated GHD (177). Evaluation of the GH-IGF-I axis could help determine the most appropriate starting dosage of rhGH. Even though most studies have not shown an increase in the incidence of neoplasms in NS patients treated with rhGH, there are no long-term studies specifically designed to address this issue. Since malignancies for patients with NS tend to involve multiple sites and develop throughout life, a routine tumor surveillance program should be implemented. In line with the authors of previously published studies (105, 110), we recommend that when rhGH therapy is initiated in NS patients, the possibility of performing a brain MRI is considered, particularly in subjects with PTPN11 mutations who appear to have higher risk for CNS neoplasms.

Published data do not show any changes in myocardial function, or in ventricular wall thickness during rhGH treatment in NS patients but the lack of genetic data means that a definite conclusion cannot be reached. In children with a diagnosis of HCM a cautious approach and careful follow-up are necessary.

In conclusion, NS is a genetic disorder with substantial clinical variability, which in part is associated with the specific genes and mutations involved. Given the genetic and clinical complexity of the disorder and high prevalence of cardiac defects and malignancies, NS requires a multidisciplinary approach and follow-up.

The overall experience with rhGH treatment in most NS patients with short stature is reassuring; the data reveal few serious adverse effects. Therapy with rhGH increases HV in patients with NS, but firm conclusions regarding the effects of this therapy on near adult height and long-term health are not available. A better understanding of the causes of short stature, as well as response to rhGH treatment in NS, is needed and must be based on genetic characterization. Reliable large-scale and case-control studies are crucial in elucidating the long-term effects of rhGH treatment and defining the examinations necessary prior to treatment and in follow-up. Until we have more complete data, an individualized follow-up and close monitoring, also related to the cardiac, neoplastic and orthopedic risks, during rhGH treatment should be considered.

Silvia Favilli, Giovanni Battista Calabri, Giulio Porcedda, Gaia Spaziani, Luciano De Simone, Elena Andreucci, Giovanna Traficante, Giorgia Mancano, Angelica Pagliazzi, Sara Bargiacchi, Giulia Gori.

All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.

MT and SS have received speakers’ bureau honoraria from Novo Nordisk. The other authors do not have any financial or non-financial competing interests in relation to this manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.