Obesity in achondroplasia patients: from evidence to medical monitoring

In achondroplasia, the development of obesity is not typical. As early as at the end of second World War, Wade H. Brown and Louise Pearce described a spontaneous rabbit model of achondroplasia with a recessive phenotype and early mortality in the first days after birth [18]. They noticed “a curious appearance due to conspicuous folds of loose, redundant skin and a very large protuberant abdomen”. In 1990, Owen et al. observed the preferential accumulation of abdominal adipose tissue in adults with achondroplasia [13]. In a retrospective study performed in children with achondroplasia, we have identified that the development of an abdominal obesity occurs very early in childhood and is exacerbated during adolescence [11]. This preferential abdominal development was confirmed in achondroplasia mice where, in spite of a similar increase in total fat mass following a high fat diet, the adipose tissue repartition was different between wildtype and achondroplasia mice, with an important increase in the development of epididymal adipose tissue in mice with achondroplasia while control mice preferentially developed an increase in subcutaneous adipose tissue [11].

Interestingly, in the context of achondroplasia, the development of a visceral obesity was not associated with the development of a diabetic profile and patients even had a tendency to lower fasting glycemia growing up [11]. Very similarly, achondroplasia mice developed an android obesity that was not associated with a diabetic profile, with fasting glycemia and lipidemia levels that were below normal ranges [11]. Our study demonstrated alterations in glucose metabolism triggered in part by abnormal pancreatic function and development. Moreover, indirect calorimetry showed an alteration in the use of glucose. Indeed, the mice carrying the mutation draw their energy preferentially from the oxidation of lipids, while the mice of the control group draw it from the oxidation of carbohydrates [11]. While surprising, these results have been suggesting almost five decades ago. In 1971, Thomas H. Shepard and his team used a spontaneous rabbit model of achondroplasia to better characterize the cartilage from a biochemical and physiological point of view, investigating glucose metabolism in cartilage explants [19]. They showed a defective glucose metabolism with no alterations in carbon dioxide and lactate production. Based on these preliminary results, in 1972, Plato J. Collipp et al. proposed to study the carbohydrate metabolism of achondroplasia patients aged from 4 months to 10 years [20]. Oral glucose tolerance tests were performed and Collipp concluded that an abnormal glucose tolerance was detected in 16 out of the 24 cases, suggesting a defect in peripheral glucose utilization. Although precautions need to be taken in interpreting these results because of the absence of an age-matched control group and the overly heterogeneity of this group of patients, they were nevertheless precursors of the observation of an alteration in glucose metabolism in patients with achondroplasia. In 2009, Alatzoglou et al. demonstrated the absence of insulin or glucose intolerance (defined as a plasma glucose concentration greater than 7.8 mmol/L 2 h after glucose bolus during oral glucose tolerance test (OGTT)) associated to low fasting insulinemia in adolescents with FGFR3 mutations [14]. However, in average size children, it was shown that, during OGTT, insulin levels reflecting insulin tolerance correlated better with the metabolic status of obese children than glucose levels [21]. Today, there is no study describing insulin levels during OGTT in achondroplasia children but, in one case of an achondroplasia child, insulin levels appear to be within normal standard range during an OGTT (unpublished data). If these results are confirmed, this observation will be consistent with Alatzoglou’s data describing normal glucose and insulin tolerance and low fasting insulinemia [14].

In the general population, the high prevalence of obesity has its origin in the interactions between genes and the lifestyle (physical activity, eating habits, sleep habit, stress, etc.). In achondroplasia however, before the obesogenic environment was installed in modern society, obesity was already described as a complication/disease common to people with this disease [10, 22]. Even today, the hypothesis that prevails between public and professional-sanitary opinion suggests that the predisposition to obesity and its high prevalence in achondroplasia people results from a problem of energy balance due to excessive caloric intake and lack of physical activity. Certainly, children with achondroplasia are limited by their psychomotor development and their physical condition [23]. In addition, the early appearance of overweight and obesity contributes to worsen a sedentary lifestyle and/or to exclude these children from the sports practiced by children their age. Moreover, it is important to take into account the permanent psychological stress that supposes to coexist with the social stigma of achondroplasia. Children with achondroplasia and obesity must face a double stigma and social exclusion, or fear of it, can also be a cause of stress, anxiety, hyperphagia, even binge eating and finally, obesity. It is true that it appears that children need to eat continuously, which significantly can contribute to an excessive caloric intake. It is necessary to better understand this phenomenon that seems of great importance, and is a reason for alarm for families, since it seems that children with achondroplasia want to eat all the time because they are always hungry. Very interestingly, this phenomenon of constant feeding has been observed in a study using a mouse model of achondroplasia. In mice, the energy expenditure and the total food intake was not modified but they have a tendency to eat constantly over a 24 h period [11]. These observations demonstrate that the phenomenon of constant eating seems to be an important factor when we considered obesity in the case of achondroplasia. It is necessary to discern if this behavior is a response to a psychological or physiological-metabolic problem, or both. Finally, scientific studies describing energy expenditure in people with achondroplasia concluded that the basal metabolism of people with achondroplasia is lower than that of people of average height of the same age and sex, but higher than expected for their height and weight [13, 24‐27]. Although none of them is conclusive, different hypotheses could explain the high metabolic rate per unit of weight in people with achondroplasia at rest as well as practicing physical activity, compared to people with standard average height. Obviously, body composition and body proportions are different between people with standard height and people with achondroplasia and it is necessary to determine the relationship between body composition and resting energy expenditure (REE) in achondroplasia. On the other hand, the anthropometric differences observed in these people determine a higher stride frequency, a higher breathing rate and a higher heart rate and, therefore, a higher REE. Similar to the population of standard height, there is great interindividual variability. In a recent study, Madsen and collaborators describe the anthropometrics, diet, and REE in a group of Norwegian adult population with achondroplasia [28]. The results revealed a high frequency of central obesity and unhealthy dietary habits. Mean energy intake was low and only 10% higher than the mean REE and does not explain the high prevalence of abdominal obesity observed. Altogether, the different studies strongly suggest that the origin of the visceral obesity in achondroplasia cannot be limited to energy imbalance.

The link between the mutation responsible for achondroplasia and the metabolic complications seems difficult to highlight because no metabolic pathology has been directly associated with a mutation on the FGFR3 receptor. Indeed, the only known pathologies whose origin is a mutation on the FGFR3 receptor are chondrodysplasias, multiple myeloma and some cancers. Achondroplasia remains one of the rare cases proving a possible relationship between FGFR3 signaling and the development of metabolic alterations. However, today, there is an increasing number of evidence suggesting that the early onset and development of this central and atypical obesity may originate in the FGFR3 mutation itself [11, 13, 20]. Using a mouse model of achondroplasia, we have recently hypothesized that an alteration in the biology of mesenchymal stem cells, that are common chondrocytes and adipocytes progenitors, could partially explain the development of obesity in the context of achondroplasia [11]. Our hypothesis is in agreement with a recent study showing that mesenchymal stem cells generated from an achondroplasia patient carrying the G380R mutation exhibited significantly reduced osteogenic differentiation and enhanced adipogenic differentiation [29]. In this sense, several studies have shown that the activation of one differentiation pathway involves an inhibition of the other one [22, 30‐32] confirming a permanent regulation loop between adipocytes and chondrocytes differentiation. Oxytocin whose receptor is present both in adipocytes and chondrocytes could play an important role in this regulation [30]. Very interestingly, in accordance with a previous study demonstrating that the inhibition of hypertrophic chondrocytes differentiation is mediated by Erk [33], the study in mesenchymal stem cells generated from a patient confirms that hyperactivation of this pathway could be responsible for the increased differentiation of adipocyte progenitor [18]. Moreover, it has been suggested that the Oxytocin action in adipocyte differentiation could be mediated by Erk1 / 2 phosphorylation [30] and it would appear that the Oxytocin - FGFR3 / Erk axis plays a key role in the establishment of the phenotype observed in achondroplasia.

Other evidence suggest that mutations in the FGFR3 receptor responsible for bone growth alterations could be associated with the development of obesity. A report presenting a case of hypochondroplasia associated with acanthosis nigricans describes high BMI associated with insulin resistance without diabetes development [34]. This increase in BMI was also observed in a 16 years old patient with hypochondroplasia (unpublished data). Therefore, it seems that some pathologies associate mutations in the FGFR3 receptor at the origin of a bone pathology and the development of obesity. In this sense, the FGFR3 receptor could be a common player in the complications observed. This hypothesis needs to be confirmed but they can offer new possibilities for the global treatment of achondroplasia.

In order to better manage obesity, it is necessary to considerer the potential nutrigenetics effect of the FGFR3 gene in the context of achondroplasia. Several molecules such as the Fat Mass and Obesity-associated protein (or alpha-ketoglutarate-dependent dioxygenase FTO), Melanocortin 4 Receptor (MC4R) or Apolipoprotein (APOE), participate in the regulation of appetite, thermogenesis, adipogenesis and can present polymorphisms allowing individualized dietary treatment according to the risk alleles carried [41]. There is little evidence available so far regarding the FGFR3 gene, therefore, recommendations for these patients should be general, since there is no optimal diet for the prevention or treatment of obesity [42].

In the context of achondroplasia, if the metabolic response to different dietary interventions is conditioned by the nutrigenetics, the question is to know what quantity and quality of macronutrients in the diet is the most appropriate. The percentage of macronutrients with respect to the total energy value of the diet may be one of the keys to dietary intervention in achondroplasia and, if this is confirmed, it would be necessary to readjust the percentages recommended of proteins, carbohydrates and fats, to their real needs. Intervention studies should be carried out to show the metabolic response after the administration of different proportions of carbohydrates, lipids and proteins in the diet. In addition to carbohydrates or fats, other nutrients or substances contained in foods with the ability to trigger or modulate the metabolic response should also be considered.

Two cases of bariatric surgery have been reported in achondroplasia patients suffering from morbid obesity, highlighting the complexity of any surgery in a pathology like achondroplasia [51, 52]. Indeed, the complications associated with achondroplasia associated with those lonked with obesity make aesthesia procedures very complex, particularly with regard to respiratory disorders secondary to a deformed airway. Although two cases have been reported, bariatric surgery is totally contraindicated in addition to its own risks because it does not guarantee results in the medium and long term. Moreover, this technique only allows secondary treatment because it does not treat obesity at its source. Psychological therapy, food education, and active life, are the most effective and realistic solution to face a problem such as obesity in the context of achondroplasia.

There are no predictive equations to estimate body fat mass in people with achondroplasia. The methods of choice for the analysis of body composition in people with achondroplasia are DEXA (dual energy X-ray absorptiometry) and magnetic resonance imaging [11, 26]. Recently, Sims and collaborators explain that, although conclusive results of whole-body or segmental body composition have not been achieved in this population group, it seems more appropriate to perform the composition of individual segments and regions to help define the clinical status of these people, instead of using whole body measurements, such as body mass index (BMI) [53]. However, in clinical practice, it is not usual to have such sophisticated equipment on hand. For this reason, anthropometric tools can still be useful in the routine monitoring of these patients.

The BMI is an height-dependent index and it can tends to overestimate body fat mass in achondroplasia patients. The BMI should be used with other complementary anthropometric measures since it does not allow quantifying fat mass or its distribution in the body. A recently published study found a strong correlation between BMI and waist circumference and describes a high prevalence of abdominal obesity that increases with age and a more sedentary lifestyle, in its group of Norwegian adults with achondroplasia [28]. However, it concluded that it is necessary to continue investigating body composition, fat distribution and its clinical implications in these people, as well as the influence that physical activity can have on these factors.

The BMI, the Rohrer index, the weight/height index, the thickness of the skin folds, the waist/hip index, the waist circumference, the fat mass and the fat-free mass are indexes, anthropometric tools and estimators of the fat mass that are available to characterized the body composition of the population with achondroplasia (Table 1). Analyzed together, they can provide information on the nutritional status and body composition of the individual, a diagnosis of the obesity situation and a proposal for adequate intervention through nutritional advice and physical activity habits. Their periodic evaluation, during the growth period can alert on situations of risk to intervene immediately and accurately [54]. Their analysis is useful for the individual follow-up of patients, but it would also be interesting to carry out a longitudinal follow-up from childhood to measure the probability of developing obesity and its comorbidities during adulthood, as well as to measure the risk of morbidity and mortality. Also, this follow-up can determine which of the anthropometric tools are most useful for the clinical management of obesity in people with achondroplasia.

The impact of obesity on the overall health of people with achondroplasia is being widely discussed recently. However, obesity prevention and treatment programs that promote the long term health improvement of these patients have not been yet established. In the absence of other scientific evidences and based on the clinical experience of the treatment of obesity in people with achondroplasia, it would be necessary to propose a multidisciplinary monitoring program that integrates the tools and therapies currently available for the prevention and treatment of obesity of people of average height, adapted to the needs of this population group.

This program must be supported by two strategies: a protocol to assess the nutritional status of people with achondroplasia from birth, with the aim of preventing the development of obesity and detecting risk situations that should be treated (Table 2). And, on the other hand, a personalized action plan for each patient with the aim to work individually the nutritional aspects (dietary / nutritional recommendations, food education and nutritional coaching), psychological therapy and sports practice, more adequate in each case. In the short term, the objectives should focus on individualized patient care. In the long term, the objectives are to promote the health and QoL of these people through the prevention and/or treatment of obesity and its possible metabolic, medical and orthopedic complications. The acquisition of healthy eating habits and the practice of physical exercise since childhood should be integrated into daily routines for the promotion of long-term health.

During the growing period, current protocols suggest annual follow-up visits. In adults, the frequency of visits can be every 2 years. Follow-up visits throughout childhood and adolescence are aimed at detecting changes that could induce a risk situation that can be treated immediately. For instance, the early development of obesity could be detected triggering the implementation of a multidisciplinary protocol with the patient’s agreement to ensure motivation and compliance. Food education must be intensified, along with psychological therapy and a reinforced physical activity plan. It could be also necessary to perform analytical evaluation of patients to study glucose metabolism, orexigenic hormones, anorexics and stress hormones, such as cortisol, and observe their relationship with obesity, stress and constant eating in achondroplasia.