Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients

Abstract Aims Rabson-Mendenhall syndrome (RMS) is a rare autosomal, recessive disorder characterized by severe insulin resistance due to mutations in the insulin receptor (INSR) gene. This study aims to analyze the clinical features and gene mutations in RMS, which have not been extensively studied. Methods PubMed, Embase, the China National Knowledge Infrastructure, and Wanfang were searched for “Rabson-Mendenhall syndrome” or “Black acanthosis hirsutism insulin resistance syndrome.” Results A total of 42 cases from 33 articles were included. The body mass index ranged from 18.50 to 20.00 kg/m2 with an average of 16.00 kg/m2. There were no overweight (25.00∼29.90 kg/m2) or obese (≥30.00 kg/m2) patients. Acanthosis was present in 29 cases (29/42, 69.05%); growth retardation in 25 cases (25/42, 59.52%); dental anomalies including absence of teeth, crowding, and malocclusion in 23 cases (23/42, 54.76%); and hirsutism in 17 cases (17/42, 40.48%). The average glycosylated hemoglobin was 9.35%, and the average fasting blood-glucose was 8.44 mmol/L; the mean fasting insulin was 349.96 μIU/mL, and the average fasting C-peptide was 6.00 ng/mL. Diabetes was reported in 25 cases (25/33, 75.76%) all of which were diagnosed before 23 years old. All 42 patients had recorded gene mutations, with 22 patients (22/42, 52.38%) having ≥ 2 mutations and 20 cases (20/42, 47.62%) having only 1 mutation. No statistical differences were found in clinical features and laboratory parameters between patients with different mutations. Conclusion The study indicates that RMS should be considered in young patients with hyperinsulinemia, hyperglycemia with low weight, acanthosis nigricans, growth retardation, dental anomalies, and hirsutism.

The human insulin receptor is composed of 2 extracellular α subunits and 2 transmembrane intracellular β subunits.The α and β subunits of the insulin receptor are encoded by a single gene (INSR) located at p13.3→p13.2 on chromosome 19's short arm.This gene consists of 22 exons and 21 introns [1].Mutations in the INSR gene have been associated with various inherited insulin resistance syndromes, such as leprechaunism, Rabson-Mendenhall syndrome (RMS), and type A insulin resistance [2].In 1956, Rabson and Mendenhall initially described a rare autosomal recessive inherited disease in 3 siblings [3], characterized by severe insulin resistance and fluctuations in blood glucose.
The clinical manifestations of Russell-Silver syndrome (RMS) encompass various physical characteristics such as coarse facial features, acanthosis nigricans, hirsutism, dental abnormalities, and growth retardation [4,5].The rarity of RMS often leads to misdiagnosis, and a comprehensive review of this condition is currently lacking.Consequently, this study aims to provide a summary of the clinical features and genetic mutations associated with RMS, with the intention of facilitating early diagnosis by healthcare practitioners.

Data Sources and Study Patients
PubMed, Embase, the China National Knowledge Infrastructure, and Wanfang databases were systematically searched from their inception until August 7, 2023, without any language limitations.The search strategies employed the following terms: "Rabson-Mendenhall syndrome" or "Black acanthosis hirsutism insulin resistance syndrome."All included studies fulfilled the following eligibility criteria: (1) patients were definitively diagnosed with RMS through DNA testing and clinical assessment; (2) the references provided either comprehensive clinical data of the probands or documented mutations in the INSR gene.The flow chart showed the identification articles included and the reasons for their exclusions (Fig. 1).
The present study examined various clinical and laboratory variables, including (1)

Statistical Analyses
The demography, clinical, and blood indicators of patients were described utilizing simple summary statistics.Variables were analyzed by t-test and Wilcoxon signed rank test.Spearman's correlation analysis was used for bivariate analysis.All tests were 2-sided, and a P-value <.05 was considered statistically significant.Statistical analysis was performed using the Statistical Package for the Social Sciences version 26 for Windows.

Drawing Tools
All the tables and figures were produced by Excel and GraphPad Prism 8.
Thirteen patients had family histories accessible: 46.15% were consanguineous; 53.85% were not; and 7 (53.85%)had a history of diabetes, hirsutism, or acanthosis nigricans in their families.The age range for the 36 patients for whom data were available was 0.00 to 23.00, with an average age of 9.41 (Supplementary Table S1) [6].Of the 8 patients for whom data were available, 37.50% (3/8) had a history of preterm birth, whereas 62.50% (5/8) were born within the expected time.
RMS is a disease caused by mutations of INSR.The INSR gene is located in 19p13.2-13.3, with a full length of 170 kb, composed of 22 exons and 21 introns.It is a tetramer of 2α and 2β subunits.Exons 1 to 11 encode α subunits, and exons 12 to 22 encode β subunits [1].Kadowaki et al [12] indicated that INSR mutations retarded the posttranslational processing of the receptor and transportation of the receptor to the plasma membrane, thereby reducing the number of receptors [13] on the cell surface.The mutation also caused a reduction in the affinity of the receptor to insulin [12] so that the mutation of INSR led to the insulin resistance of the target cell.
Insulin resistance is defined as the inability of target tissues to mount a normal coordinated glucose-lowering response at a normal plasma insulin level, including suppression of endogenous glucose production, inhibition of lipolysis, cellular uptake of available plasma glucose, and net glycogen synthesis.It is considered to be a driving factor in many diseases such as metabolic syndrome, nonalcoholic fatty liver disease, atherosclerosis, and type 2 diabetes [14,15].To overcome the suboptimal action in insulin-targeting tissues, organisms have to produce a large amount of insulin; thereby hyperinsulinemia develops.Hyperinsulinemia is typically observed early in the lives of RMS patients [16,17].A previous study reported an RMS patient who initially had hyperinsulinemia, but his insulin levels gradually decreased, and finally the proband died due to ketoacidosis [1].
Previous studies have found that high insulin levels contribute to body fat accumulation, leading to an increase in BMI [18].However, our study found that all RMS patients had hyperinsulinemia but were not obese, and some were even underweight.On the one hand, INSR encodes 2 isoforms (INSR-A and INSR-B) depending on the exclusion or inclusion of 12 amino acids in the C-terminal domain, respectively.INSR-A is predominantly expressed in undifferentiated cells and contributes to prenatal development and tissue growth, whereas INSR-B is enhanced in postmitotic and differentiated cells, largely responsible for the systemic metabolic effects of insulin in adults [19].The role of the different INSR isoforms in the development and function of human adipocytes has not yet been fully clarified.However, the distinct distribution of INSR isoforms on the cell surface may lead to different metabolic effects of insulin in adipocytes and other cells [20].Insulin could increase the uptake of glucose by recruiting glucose transporters to the plasma membrane of adipose cells and potently stimulate lipogenesis by activating lipogenic and glycolytic enzymes through covalent modification [21].At the same time, insulin can also inhibit the activity of lipase and reduces fat breakdown [22].On the other hand, insulin resistance can lead to hyperinsulinemia.However, the reduced number of insulin receptors and decreased affinity with insulin detract from the weight gain effect of insulin, which may result in hyperinsulinemia and nonobesity in RMS patients [23].
Our study showed that all patients were diagnosed as RMS patients before 23 years old with an average of 9.41 years old.Longo et al reported a minimum survival time of 9 ± 1.4 years for RMS patients, which is much lower than that for type 2 diabetes patients [24].It was a pity that our study did not analyze the survival times of patients due to the lack of available information.
Acanthosis nigricans results from long-term exposure of keratinocytes to insulin [25].High levels of insulin stimulate IGF receptors, thereby promoting the proliferation of keratinocytes.As mentioned, the short isoform (INSR-A) is expressed in undifferentiated cells and contributes to prenatal development and tissue growth.
It was found that RMS patients were likely to grow slowly.Height and weight below the median of the normal reference values for children of the same age and sex, minus 2 SDs or below the third percentile, are considered as growth retardation [26].The relationship of growth retardation and INSR mutations is still unknown.However, high insulin levels in patients may interact with IGF-I receptors and provide a feedback mechanism for reducing GH secretion [27].
The exact mechanisms responsible for dental problems of RMS patients remain unclear.However, it may be relative to hyperglycemia and hyperinsulinemia environments.A study showed that disturbances in the developing occlusion may be caused by delayed tooth eruption, accelerated tooth eruption, or altered sequence of eruption [28].Proinflammatory caused by diabetes contributed to a reduction in both the quality and quantity of peri-tooth bone and shortens the eruption distance [28].A previous study has reported that children with diabetes mellitus exhibit accelerated tooth eruption corresponding to a late stage of tooth eruption [29].In addition, optimal salivary flow rate contributes to a protective environment against dental caries and periodontitis.However, hyperglycemia increased the risk of hyposalivation and thereby was related to caries and periodontitis [30].When it comes to children in a period of growth, the development of teeth would be influenced.A previous study found that after insulin treatment, the proliferation ability of osteoblasts was weakened and the number of osteoblasts was significantly reduced [30].However, the exact effect of excessive insulin on tooth development remains unknown and requires further research.Some case reports mention treatment methods for RMS patients, such as oral metformin, SGLT2, insulin injection, concentrated insulin, concentrated (U-500) insulin, metreleptin (recombinant human methionyl leptin), and recombinant IGF-1.However, due to the rarity of the disease, there are currently no randomized controlled trials for related treatments, making it difficult to accurately evaluate the effectiveness of various treatment methods.Conventional diabetes treatments such as lifestyle modification, insulin or secretagogues, and insulin sensitizers are insufficient for achieving adequate glycemic control in most RMS patients, and their extreme insulin resistance limits the efficacy of high-dose insulin [31,32].Novel agents have been attempted.Metreleptin improved glycemia over 1 year in RMS patients [33].Leptin is a major signal of satiety, and metreleptin is a kind of recombinant methionyl human leptin, which has been shown to improve insulin-stimulated hepatic and peripheral glucose metabolism in severely insulin-resistant lipodystrophic patients.Metreleptin subcutaneously injection in patients with congenital leptin deficiency and lipodystrophy decreased food intake and energy storage and altered central nervous system activity in regions associated with hunger and satiety, which might be the mechanisms by which metreleptin improves glucose in RMS [33,34].Besides, in rodent models of lipodystrophic syndromes, several mechanisms may be relevant.This includes activation of 5-AMP kinase, which will increase insulin sensitivity.In addition, leptin therapy may affect insulin receptor substrates, such as insulin-2, directly or indirectly by reducing endogenous hyperinsulinemia.However, there are no clear rodent models for RMS, which make it difficult to prove the efficiency of the therapies [35,36].
Our study has several limitations.First, all articles were limited to the literature with available diabetes-related indicators, which might lead to selection bias.Second, due to the low prevalence of RMS, it is challenging to analyze some rare clinical manifestations.Therefore it is possible to get a negative result indicating that single or multiple mutations were not significant in indicating the severity of the disease.Further research is needed to better understand RMS.
In summary, RMS is often misdiagnosed due to its low prevalence, and there is currently no comprehensive review available.Our study systematically analyzed the clinical features and genetic mutations of 42 patients in 33 articles.For the young with hyperinsulinemia, hyperglycemia with low weight, acanthosis nigricans, growth retardation, and dental anomalies, RMS should be considered, and genetic testing is suggested in order to differentiate RMS from other types of insulin resistance syndromes.
country and area of origin; (2) age at the time of diagnosis; (3) sex; (4) body mass index (BMI); (5) familial history; (6) clinical characteristics; (7) diabetes therapy, encompassing oral hypoglycemic agents, insulin, and dietary interventions; (8) laboratory test results at the time of diagnosis, encompassing fasting plasma glucose, fasting insulin, 2-hour postprandial plasma glucose, 2-hour postprandial insulin, glycosylated hemoglobin; and (9) identification of amino acid substitutions and mutations, along with their respective types and locations within each gene.

Figure 1 .
Figure 1.Literature review inclusion process.The number of records identified through database searches was 642.After removing duplicates and unrelated research there were 141 references left.After screening according to inclusion criteria, a total of 33 articles were ultimately included in the study.