Rabson-Mendenhall syndrome caused by a novel splice-site mutation (c.1123+2 T>C) of insulin receptor: A case report and review of literature

Abstract

BACKGROUND

Rabson-Mendenhall syndrome (RMS) is an extremely rare monogenic form of diabetes caused by mutations in the insulin receptor (INSR) gene, with only about 50 cases reported worldwide to date. Here, we report a case of RMS caused by a previously unreported c.1123+2 T>C splice mutation.

CASE SUMMARY

The patient was diagnosed with acanthosis nigricans and hypertrichosis at birth, and the growth rate was slower than that of normal children. At age 5, the patient had severe hyperinsulinemia, congenital heart abnormalities, and pineal cysts. At age 13, he was diagnosed with diabetes and exhibited symptoms of hyperinsulinemia, low body weight, growth retardation, acanthosis nigricans, dental anomalies, an oversized penis, and a pineal cyst. Sequencing results indicated an INSR c.1123+2 T>C mutation, and bioinformatic analysis suggested that this mutation led to splicing abnormalities, thereby affecting INSR function. Both parents carried the mutated gene, whereas his brother had a normal genotype.

CONCLUSION

Genetic diagnosis is vital in RMS; c.1123+2 T>C mutation of INSR causes pancreatic decline; current treatments show limited effectiveness.

Key Words: Rabson-Mendenhall syndrome; Insulin receptor gene; Splice mutation; Hyperinsulinemia; Case report

Core Tip: Rabson-Mendenhall syndrome is a rare monogenic diabetes caused by insulin receptor gene mutations, with no effective treatment currently available. Early diagnosis is essential for treatment planning and prognosis evaluation. We report a case of Rabson-Mendenhall syndrome where clinical features, whole-exome sequencing, and bioinformatics identified the c.1123+2 T>C mutation as likely pathogenic. Due to severe insulin resistance, a combination of oral hypoglycemic agents with different mechanisms may be appropriate. Novel therapies, such as leptin, hold potential for future research.

INTRODUCTION

Rabson-Mendenhall syndrome (RMS) is a monogenic type of diabetes that falls under the category of special types of diabetes[1]. The incidence of RMS is extremely low, with only scattered case reports found in the domestic and international literature. The first report of RMS dates back to 1956, when Rabson and Mendenhall described three siblings with this condition[2]. To date, we have reviewed only over 50 case reports of RMS[3]. It is a rare autosomal recessive genetic disorder caused by mutations in the insulin receptor (INSR) genes. Typical characteristics of RMS include severe insulin resistance in monogenic diabetes, including low birth weight, thickened nails, hypertrichosis, acanthosis nigricans (ANs), dental protrusion and dysplasia, polycystic ovaries, abdominal distension, penile enlargement, pineal cysts, and insulin-resistant diabetes[4-8]. This is the only insulin-resistant syndrome known to present with dental abnormalities.

Here, we report the case of a Chinese patient with classical manifestations of RMS resulting from a novel intronic mutation, INSR (NM_000208.4, c.1123+2 T>C). This novel intron mutation, located at the junction of exon 4 and intron 4, may cause variable splicing of INSR, ultimately resulting in the impaired function of INSR.

CASE PRESENTATION

Chief complaints

This report describes the case of a 13-year-old boy who had AN for 13 years and polyuria and polydipsia for 5 years.

History of present illness

In 2019, when the patient was 13 years old, he was scheduled for surgery due to “snoring during sleep for one year and enlarged tonsils for six months”. During hospitalization, elevated blood glucose levels were detected, and the patient was transferred to the endocrinology department for further examination. Glycated hemoglobin was 8.6%, and urinalysis showed glucose 3+ and ketone bodies 1+. Pancreatic function is detailed in Table 1. The 24-hour urine protein was 225.4 mg/24 hours and IGF-1 was 127.63 ng/mL. Tests for insulin autoantibody, islet cell cytoplasmic antibodies, and glutamic acid decarboxylase antibody were negative. Due to AN, severe insulin resistance, and malocclusion, the patient was diagnosed with RMS.

Table 1 Results of the follow-up in the past 5 years.

Time	Fasting C-peptide (ng/mL)	Postprandial C-peptide (ng/mL)	Fasting insulin (IU/mL)	Postprandial insulin (IU/mL)	HbA1c	Urine sugar	Urine ketone bodies
2011	8.09	25.32	272.4	> 1000	5.6%	+	+
2019	7.67	22.37	328.36	327.99	8.6%	3+	4+
2022	7.17	20.2	> 200	> 200	13%	4+	4+
2023	4.9	17.8	> 200	> 200	12.6%	3+	4+
2024	4.5	16.7	> 200	> 200	11.2%	3+	4+
2025	3.07	14.3	> 200	> 200	11.5%	2+	3+

HbA1c: Glycated hemoglobin A1c.

History of past illness

The patient’s parents were un-consanguineous. He was born at term (2006) with normal birth weight and length. At birth, he exhibited darkened skin and hypertrichosis primarily on the back of the neck and limbs. AN was observed on the neck, armpits, elbows, groin, navel, and popliteal fossa. In September 2011, at the age of 5 years, he was examined at Beijing Children’s Hospital, where an II/6 grade systolic murmur was heard over the precordium. Further examination revealed the blood glucose levels and pancreatic function (Table 1). Thyroid function, blood biochemistry, cortisol, adrenocorticotropic hormone, luteinizing hormone, follicle-stimulating hormone, prolactin, thyroglobulin antibody, thyroid peroxidase antibody, and thyrotropin receptor antibody levels were all within normal ranges. Cardiac ultrasonography revealed congenital heart defects, including a ventricular septal defect (subcritical) and atrial septal defect (ostium secundum). Pituitary magnetic resonance imaging suggested a pineal cyst, and abdominal and adrenal ultrasonography, adrenal computed tomography, and electrocardiogram showed no significant abnormalities. Diagnoses included: (1) AN; and (2) Congenital heart disease. No special treatment was administered at that time, as the child’s blood glucose level was not elevated.

Personal and family history

The patient also had a younger brother. His parents and brothers did not have diabetes or any other hereditary diseases.

Physical examination

In 2019, his height was 150 cm (-2 SD), weight was 34.5 kg (-2 SD) and body mass index was 15.3 kg/m². Physical examination revealed generalized AN with hypertrichosis, AN in the skin folds, loose skin, prominent and thick lips, macroglossia, and malocclusion (Figure 1).

Figure 1  Clinical imaging.

Laboratory examinations

The patient’s recent glycated hemoglobin levels, pancreatic function, and urinalysis results are shown in Table 1. The 24-hour urine protein was 225.4 mg/24 hours. Estimated glomerular filtration rate was 160 mL/minute/1.73 m². The patient had a homozygous mutation (c.1123+2 T>C) in intron 4 of the INSR gene on chromosome 11. Both parents had heterozygous mutations (c.1123+2 T>C) at this locus, while the patient’s brother was wild-type (c.1123+2 TT; Figure 2).

Figure 2 Pedigree and Sanger sequencing of the family. A: Pedigree of the Rabson-Mendenhall syndrome family; B: Sanger sequencing; C: Conservation analysis of mutation site insulin receptor c.1123+2.

Imaging examinations

Abdominal ultrasonography revealed an enlarged spleen and kidneys, and testicular ultrasonography revealed multiple hyperechoic spots in both testes. Cardiac ultrasonography revealed patent foramen ovale and mild tricuspid regurgitation. Magnetic resonance imaging of the brain revealed a pineal cyst and adenoid hypertrophy. Pituitary magnetic resonance imaging showed a linear abnormal signal in the lower part of the pituitary gland.

FINAL DIAGNOSIS

Based on the patient’s medical history, symptoms, signs, laboratory tests, and genetic sequencing results, he was diagnosed with rhabdomyosarcoma and diabetic kidney disease (stage G1A2).

TREATMENT

After admission to our department, the patient was treated with a combination of metformin and continuous subcutaneous insulin infusion via an insulin pump to control blood glucose, ultimately reaching a metformin dosage of 0.5 g (three times a day); insulin pump basal rate of 16 units, with pre-meal boluses of 8 units, 10 units, and 10 units; fasting blood glucose maintained around 6 mmol/L and postprandial blood glucose between 8-10 mmol/L. The patient was then transferred to the Department of Ear, Nose, and Throat for surgical treatment. Postoperatively, the patient was treated with Novolex 30 (10 units before breakfast, 8 units before dinner) to control blood glucose, and the blood glucose control was 5-6 mmol/L fasting blood glucose and 6-8 mmol/L postprandial blood glucose. After discharge, the patient was prescribed subcutaneous injections of insulin glargine 16 units and aspart 8 units, 10 units, and 10 units before meals, with blood sugar control as previously described.

In 2022, the patient was treated with insulin glargine and insulin to control blood glucose levels. From 2022 to 2024, the patient was treated with insulin glargine (100 units) and insulin aspart 30 units, 30 units, and 30 units before meals to control blood glucose. Starting in 2024, the patient’s plan was changed to metformin, voglibose, sitaglitazone, and empagliflozin to control blood sugar. Currently, the fasting blood sugar level was approximately 6 mmol/L, and the postprandial blood sugar level was 10-20 mmol/L, which was closely related to the patient’s irregular diet.

OUTCOME AND FOLLOW-UP

The results of the follow-up over the past 5 years are shown in Table 1.

DISCUSSION

Bioinformatics analysis

The predicted results of the Rare Disease Data Center RNA splicer (https://rddc.tsinghua-gd.org/)[9,10] indicated that c.1123+2 T>C can generate two splicing modes: (1) Splicing mode 1: Splicing at a new position on the exon of RNA leads to the deletion of the exon sequence; and (2) Splicing mode 2: The original splicing recognition site was disrupted using potential alternative splicing positions in introns, ultimately resulting in the partial inclusion of intron sequences. The possible splicing sites were c.1123+930, c.1123+1038, c.1124-819 (Figure 3A).

Figure 3 Rare Disease Data Center tool prediction and abnormal structure analysis of possible RNA splicing results. A: Splicing mode 1: Splicing at a new splicing position on the exon of RNA leads to deletion of the exon sequence. Splicing mode 2: The original splicing recognition site was disrupted, using potential alternative splicing positions in introns, ultimately resulting in partial inclusion of intron sequences. The possible splicing sites are c.1123+930, c.1123+1038, c.1124-819; B: The protein structure of wild-type and mutant insulin receptor; C: Predicting insulin receptor protein structure through splicing mode 1; D: Predicting insulin receptor protein structure through splicing mode 2. INSR: Insulin receptor.

Compared to the wild-type protein, the secondary structures of the two splice mutation modes proteins showed significant changes (Table 2): The α-helices, β-sheets, β-turns, and random coils in the two splice mutation modes were significantly reduced. The spatial configuration of the wild-type INSR protein modeled by the Alphafold3 software also exhibited significant abnormalities compared to the predicted spatial configuration after the point mutation (Figure 3B-D). This suggests that c.1123+2 T>C was likely the pathogenic site for this patient, which needs to be verified through subsequent basic experiments.

Table 2 The secondary structures of the two splice mutation modes proteins, n (%).

Mutation	Total amino acid, n	α-helix	β-fold	β-turn	Random coil
Wild-type	1382	299 (21.64)	249 (18.02)	52 (3.76)	782 (56.58)
MT1	329	59 (17.93)	52 (15.81)	11 (3.34)	207 (62.92)
MT2	394	86 (21.83)	62 (15.74)	14 (3.55)	232 (58.88)

MT: Mutant type.

RMS: Diagnosis and novel INSR mutation

The most notable physical abnormality in this patient was AN, which was first reported and named by Pollitzer in 1890. AN is a keratinizing skin disorder characterized by hyperpigmentation, thickening, and a velvety texture that primarily affects skin folds, such as the neck (99%), armpits (73%), and groin[11]. Several classification methods exist for Curt-classified AN into benign (obesity-related, genetic, and endocrine) and malignant (tumor-associated) types[12]. According to Curt’s classification, our patient had no malignant tumors or related histories, suggesting a benign type. The patient did not present with obesity or other genetic syndromes; therefore, endocrine-type AN was considered. Benign AN is primarily caused by insulin resistance or defects in fibroblast growth factor[11]. Mutations in fibroblast growth factor receptor 3 lead to associated skeletal dysplasia, including Crouzon syndrome with AN[13], lethal type 1 thanatophoric dysplasia[14], severe achondroplasia with developmental delay and ANs[15], achondroplasia[16], and hypochondroplasia[17]. The patient did not have skeletal dysplasia. Combined with multiple laboratory test results indicating hyperinsulinemia, AN was considered to be caused by insulin resistance.

Severe hereditary insulin resistance can be divided into two main categories based on its cause: INSR defects and lipodystrophy[18]. Upon physical examination, no significant lipodystrophy was observed, suggesting that the patient’s insulin resistance was related to INSR defects. Whole-exome sequencing of the patient revealed a splice mutation in intron 4 of the INSR gene, which was validated by Sanger sequencing, further supporting our diagnosis. Diseases caused by insulin resistance due to INSR defects mainly include type A Donohue syndrome, RMS, and type B insulin resistance.

Type A insulin resistance is an autosomal dominant disorder that is rarely reported both domestically and internationally and predominantly observed in adolescent females aged 8-30 years. These individuals do not typically present with obesity or lipoatrophy. The main clinical manifestations include severe insulin resistance, hyperandrogenism, and AN[19]. In some cases, polycystic ovarian syndrome-like features may be present, and some patients may ultimately develop diabetes. However, diabetes is generally mild and patients can survive into adulthood[19]. Only approximately 10% of patients with type A insulin resistance syndrome have mutations in INSR, whereas mutations in other genes, such as those encoding nuclear lamin A, can also cause type A insulin resistance.

Donohue syndrome was first described in 1954 as an autosomal recessive disorder[20]. Its characteristics include severe intrauterine growth retardation, and most affected infants die during infancy. The name is derived from the distinctive elfin features observed at birth, such as short stature, wide-set eyes, low-set ears, thick lips, a flat nose, and other features, including emaciation, paucity of subcutaneous fat, hirsutism, AN, and developmental delay. These individuals also present with impaired glucose regulation and hyperinsulinemia and may exhibit fasting hypoglycemia and postprandial hyperglycemia early on. As the disease progresses, pancreatic β-cell function gradually diminishes, leading to ketoacidosis or death owing to various complications. Donohue syndrome has a very low incidence rate, with over 90% of affected children dying before the age of 2 years, which accounts for the rarity of reports.

RMS is an autosomal recessive genetic disorder primarily caused by compound heterozygous mutations in the INSR gene. It was first reported and named after Rabson-Mendenhall in 1956[2]. Its clinical features include AN, hypertrichosis, growth retardation, reduced subcutaneous fat, dry skin, thickened skin, abnormal facies, bow-shaped lips, premature dentition with incomplete dental development, fissured tongue, thickened nails, joint hyperextension, enlarged external genitalia or precocious puberty, and pineal gland hyperplasia. Some children may present with renal malformations and cardiac abnormalities. All patients exhibited severe hyperinsulinemia with some progression to diabetes, ketoacidosis, or even death. The typical clinical course includes fasting hypoglycemia and postprandial hyperglycemia before the age of 1 years, persistent hyperglycemia between the ages of 3 years and 4 years, and diabetic ketoacidosis, usually during early childhood. Most patients die of intractable diabetic ketoacidosis during adolescence. Lifespan correlates with the residual binding capacity of mutant INSR, with insulin levels declining to undetectable levels over time. Most children survive for 5 years and 15 years. RMS is the only insulin syndrome that is associated with dental abnormalities.

Type B insulin resistance is a disease syndrome centered on severe insulin resistance, primarily caused by the presence of specific anti-INSR antibodies in the circulation[21]. Typical clinical manifestations include severe hyperglycemia or refractory hypoglycemia, AN, hyperandrogenemia, and autoimmune diseases, such as systemic lupus erythematosus, scleroderma, and overlap syndrome. It is a rare form of diabetes, with fewer than hundred cases reported worldwide, and domestic research is limited to case reports.

The patient presented with significant dental misalignment, pineal gland hyperplasia, and congenital heart anomalies, suggesting a diagnosis of RMS. In RMS, severe insulin resistance is caused by defective INSRs. INSR gene mutations associated with RMS were first reported in 1990[22]. Subsequent reports of INSR gene defects include missense mutations, nonsense mutations, insertions, deletions, and complex rearrangements, with missense mutations being the most common (Table 3)[23,24]. Genetic analysis revealed a novel intron 4, c.1123+2 T>C variant of the INSR gene, which has never been recorded in public mutation databases, such as ClinVar[25], Genome Aggregation Database[26], and Human Gene Mutation Database[27]. Fortunately, the patient’s younger brother’s genotype was homozygous for the wild type, and there was no risk of developing the disease. This particular variant adds to the growing catalog of INSR mutations and underscores the genetic heterogeneity of RMS, which may have implications for genetic counseling and management strategies for patients and families.

Table 3 Insulin receptor mutations and clinical feature of Rabson-Mendenhall syndrome patients.

Mutation type	Amin acid change	Clinical feature	Ref.
Missense	Pro193 Leu	Low birth weight, failure to thrive, hypotrichosis, clitoromegaly, and relatively coarse facies	Carrera et al[30]
Missense	Ile116Thr/Arg1131Trp	Early extreme hyperinsulinemia that declines over time; severe insulin resistance, growth retardation, acanthosis nigricans, dental anomalies, hyperglycemia and ketoacidosis risk	Longo et al[31]
Missense	Pro970Thr/Arg1131Trp	Hyperinsulinemia, growth retardation, acanthosis, dental anomalies, early-onset diabetes	Longo et al[32]
Missense	Asn878Ser/Ala1162Val	Severe insulin resistance with marked hyperinsulinemia, acanthosis, growth delay, dysmorphic dentition; refractory hyperglycemia requiring multi-drug and high-dose insulin therapy	Moreira et al[33]
Missense	Cys159Phe/Arg229Cys	Extreme insulin resistance, short stature, severe acanthosis, hypertrichosis, dental abnormalities, early-onset hyperglycemia	Thiel et al[34]
Missense	Arg209His/Gly359Ser	Markedly reduced receptor, extreme insulin resistance, short stature, severe acanthosis, hypertrichosis, dental anomalies, early diabetes, recurrent infections	Tuthill et al[35]
Missense	Arg86Term; Asp261-Leu262 Ins Leu His Val	Severe insulin resistance, hyperinsulinemia, growth retardation, acanthosis nigricans, dental dysplasia, early-onset diabetes	Müller-Wieland et al[36]
Missense/deletion	IVS4-2 A>G/c.2480-2487del	Profound insulin resistance, hyperinsulinemia, failure to thrive, acanthosis, dental and nail abnormalities, early-life diabetes	Kadowaki et al[37]
Missense	Cys279Arg	Child with RMS: Extensive acanthosis nigricans, skin tags, hypertrichosis, short stature, abdominal distension, clitoromegaly, hyperinsulinemia and hyperglycemia	Duraiswamy et al[38]
Missense/deletion	Arg145Cys/19p13.2del 237kbp	Adult RMS misdiagnosed as T1DM: Severe insulin resistance, malnutrition/Low BMI, acanthosis, prognathism, dysmorphic features, diabetic complications (retinopathy)	Almotawa et al[39]
Missense/deletion	Pro1131Arg/c.4007_4010delAGAG	Infant with generalized acanthosis, growth retardation, dysmorphism, hypertrichosis, fasting hypoglycemia with hyperinsulinemia	Yan et al[40]
Missense	Arg1119Trp/del243Kb(chr19:7150507-7152938)	Severe insulin resistance, hyperinsulinemia, growth retardation, acanthosis, dental anomalies, early diabetes	Chen et al[41]
Missense	Arg141Trp	Marked hyperinsulinemia, acanthosis, growth failure, dental/skin findings, insulin-resistant diabetes requiring complex therapy	Bastaki et al[42]

Pro: Proline; Leu: Leucine; Ile: Isoleucine; Thr: Threonine; Arg: Arginine; Trp: Tryptophan; Asn: Asparagine; Ser: Serine; Ala: Alanine; Val: Valine; Cys: Cysteine; Phe: Phenylalanine; His: Histidine; Term: Termination; Asp: Aspartic acid; Ins: Insertion; His: Histidine; RMS: Rabson-Mendenhall syndrome; T1DM: Type 1 diabetes mellitus; BMI: Body mass index.

There is currently no unified treatment protocol for RMS. Research suggests that the dysfunction of the novel INSR G359S variant is largely due to abnormal receptor processing, rather than mutations inherently impairing signal transduction. This implies that the pathogenic mechanisms of different mutations may be heterogeneous, subsequently influencing the clinical phenotypes and treatment responses (e.g., insulin dose requirements). Recombinant methionyl human leptin therapy has shown definitive efficacy in treating severe insulin resistance associated with metabolic syndrome and low leptin levels, with corresponding improvements in glucose and insulin tolerance during leptin treatment[28], indicating that individualized treatment targeting the underlying cause or metabolic state may have practical applications.

There has been a case report of a 19-year-old male with RMS who developed diabetic ketoacidosis and required an insulin dosage of up to 500 U/hour (10.6 U/kg/hour). Initially, the patient’s insulin infusion was mixed with U-100 regular insulin. However, to minimize the volume, the product was combined with U-500 insulin. Diabetic ketoacidosis was eventually managed at infusion rates of 400-500 U/hour[29]. However, our case did not present such extreme dose requirements in 2019. Possible reasons include: (1) The c.1123+2 T>C variant may have a weaker impact on INSR function or mainly affects receptor processing without completely losing signaling; and (2) The younger age at onset and shorter disease duration may allow pancreatic β-cells to maintain compensatory function. Our follow-up indicated that, as the disease progressed, pancreatic function gradually declined, insulin usage increased annually, and blood glucose control worsened, consistent with the aforementioned speculation.

This case highlights the importance of early molecular diagnosis and family screening in patients with RMS to characterize mutations and inform prognostic assessments. Concurrently, long-term monitoring of pancreatic function and treatment intensity is crucial, with careful attention to the risk of progression requiring high-dose insulin or the development of diabetic ketoacidosis. In terms of functional studies, further in vitro expression/processing and signaling pathway assessments of rare variants, such as c.1123+2 T>C, should be conducted to clarify their pathogenic mechanisms and provide a basis for individualized treatment (such as leptin replacement or other targeted strategies).

CONCLUSION

The current evidence (in line with American College of Medical Genetics and Genomics guidelines) is based on computational predictions and co-segregation within the pedigree (parents as carriers, brother as wild-type), but lacks direct functional evidence, such as in vitro splicing assays, to definitively confirm that this mutation causes aberrant splicing. This case highlights the importance of early genetic diagnosis in rare metabolic disorders, such as RMS, particularly in identifying novel mutations that impair receptor function. Long-term management remains challenging as the pancreatic function deteriorates. Continued monitoring of patients with RMS is crucial for adapting treatment strategies to prevent complications, such as diabetic ketoacidosis.