Keywords
insulin resistance type A - Rabson–Mendenhall syndrome - RMS
Introduction
Insulin resistance is one of the most challenging conditions, and it is identified
as an unexpected subnormal response to endogenous and/or exogenous insulin. Commonly,
insulin resistance is diagnosed in obese patients because of the variable abnormality
spectrum of glucose homeostasis, which leads to abnormal glucose metabolism.[1]
Rarely severe insulin resistance is found with genetic syndromes. Abdominal obesity,
particularly accompanying insulin resistance on peripheral glucose and fatty acid
utilization, leads to type 2 diabetes. While in severe insulin resistance syndromes,
patients usually present with hyperglycemia notwithstanding very high doses of insulin
due to insulin receptor dysfunction. The insulin resistance secondary to genetic mutations
shares a similar clinical picture, and patients with the genetic syndromes characteristically
have intense insulin resistance along with some severe phenotypes.[2]
Rabson–Mendenhall syndrome (RMS) is a rare autosomal disorder marked by severe insulin
resistance associated with various phenotypic manifestations. A severe insulin-resistant
type of diabetes was first reported by Mendenhall in 1950; postmortem hyperplasia
of the pineal gland was described in the child.[3] In 1956, Rabson et al identified RMS in three children with familial hypertrophy
of the pineal gland and diabetes mellitus.[4] Later in 1975, West et al described two siblings with similar clinical features
associated with dysmorphia.[5] Patients with RMS survive early childhood but have a significantly reduced life
expectancy and may die during adolescence or early adulthood. However, one case study
from Spain reports on long-term survival in a patient with RMS.[6] The changes in RMS are much faster than in patients with type 2 diabetes mellitus.[7]
Case Presentation
We report the case of a 15-year-old female with poorly controlled diabetes. The girl
was presented in diabetic ketoacidosis (DKA) at the age of 50 days, and her genetic
study showed a homozygous mutation for R141W in the INSR gene, known to cause RMS.
A strong family history of RMS in her mother's cousins (one affected and two carriers)
was noted.
She was a full-term baby, born by caesarian section with a birth weight of 2.19 kg,
and required 10-day admission to the neonatal unit. She was readmitted on day 50 in
DKA. Her insulin level was high at 737 μIU/mL, insulinoma antigen 2 and glutamic acid
decarboxylase antibodies were negative, and C-peptide was > 18 ng/mL (5.99 nmol/L).
After recovery, the patient's blood glucose level was stabilized on a very high dose
(200–300 IU/day) of concentrated insulin through continuous subcutaneous insulin infusion
(CSII); oral rosiglitazone was added after 2 months. This treatment was continued
for 6 years, after which oral mecasermin replaced rosiglitazone.
From 6 to 12 years old, she had four further episodes of DKA associated with acute
infections—right lobar pneumonia, cellulitis of the abdominal wall, acute gastroenteritis,
and lipohypertrophy, respectively. In each episode, she required high doses of intravenous
insulin infusion (up to 5 IU/kg/hour). Her CSII treatment led to the development of
severe lipodystrophy at the cannula insertion sites; this has led on two occasions
to quick switching of her CSII to multiple daily injection therapy; glargine 300 IU
daily, lispro 20 IU three times a day along with mecasermin, and SGLT2 inhibitor.
Recently, she had a further two episodes of DKA precipitated by severe methicillin-resistant
Staphylococcus aureus septicemia and unnoticed pump failure; it was managed as usual
with very high doses of intravenous insulin infusion.
From 2020 to 2021, the patient was on combined therapy of mecasermin 25 units subcutaneously
twice daily and oral dapagliflozin 10 mg once daily along with CSII, Medtronic 640
using insulin lispro (the total daily dose is 261 units /day (4.6U/kg/day) with insulin
to carbohydrate ratio of 1:3 g, and insulin sensitivity factor of 1:20 mg/dL. A trial
of recombinant human leptin was not adequate and was stopped.
Currently, she is being treated with dapagliflozin/metformin 10/1,000 mg tablet (Xigduo)
and shifted to CSII hybrid closed-loop system (Medtronic 780G) to improve her glycemic
control, insulin resistance, and quality of life. Despite intensified therapy, team,
and family support, her glycemic control remains poor, with an average blood glucose
of 304 ± 86 mg/dL and hemoglobin A1c of 10.8 ± 1.2%.
Our patient's suffering started soon after birth. However, the problems list has increased
and become more complicated over the last 5 years, as summarized in [Table 1].
Table 1
List of all the issues our patient has faced over the last 5 years
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Abbreviations: COVID-19, coronavirus disease 2019; DKA, diabetic ketoacidosis; IGF1,
insulin-like growth factor 1.
Discussion
Insulin resistance is one of the most serious issues RMS patients face; therefore,
glycemic control is a challenging process in the management course of these patients.
A mutation in the INSR gene causes severe compromise of insulin receptor (INSR) function
in RMS. An interaction between insulin and insulin-like growth factor 1 (IGF1) receptors
causes a noticeable delay in linear growth and failure to thrive. The patient presented
with high fasting and post prandial blood glucose level despite the very high insulin;
this can be explained by the improper hepatic insulin clearance or hepatic steatosis
in patients with RMS due to INSR dysfunction.[8]
This patient was tried on so many medications to reduce insulin resistance, and most
of the medications failed, although each time, the failure was related to the ineffectiveness
of the medication. However, compliance issues could not be ruled out.
Frequent hospital visits due to multiple issues and requiring different specialties
and subspecialties were a considerable burden to the family, requiring a lot of time,
money, and effort. Our team tried to reduce this burden by combining five to six specialties'
appointments on the same day. Pump clinic multidisciplinary team (MDT) room in where
(in The Imperial College London Diabetes Centre- Abu Dhabi) the endocrinologist, dietician,
diabetes educator, and psychologist sat next to each other, while the nephrologist,
cardiologist, retinal camera examination, and ophthalmologist were in the same building.
The school nurse was contacted regularly by our diabetes educators, and issues were
discussed with the patients and parents in our pump MDT clinic.
Another issue faced by our patient was the systemic development of lipohypertrophy
and high consumption of pump accessories due to high insulin volume requirement. We
have tried to reduce the insulin valium used by this patient (hence, reducing lipohypertrophy
and consumption of pump accessories) by using concentrated insulin. However, after
discussing the idea with the pump technology team, this was not possible due to safety
issues, and our request was passed to the team dealing with the pump logarithm. The
technology team may need to improve their pumps' algorithm to suit patients requiring
concentrated insulin. The insurance team was approached, the consumption of insulin
and pump consumables was discussed, and we managed to get the approval process easier
and faster. Our nurses were instructed to take extra blood samples each time we needed
to do annual review blood tests, and the mother was asked to check her subsequent
appointments with other specialties if any blood test was needed to avoid unnecessary
frequent pricks.
Despite the initial resistance of the patient and her mother to see a psychologist,
consent to refer the patient to our psychologist was obtained, and our psychologist
and psychiatrist dealt with all psychological issues.
RMS patients have a significantly reduced life expectancy and may die during adolescence
or early adulthood. However, increasing awareness among health care professionals
and providing the best available treatment may improve these patients' long-term survival
and quality of life. The lack of a control group is the main limitation of the study.
Therefore, further research on the management of RSM patients is required.
Conclusion
Although RMS is very rare, however, its management is very challenging. Life expectancy
is short, with early mortality due to diabetes-related complications resulting from
severe insulin resistance and poor glycemic control.
Knowing the list of the expected issues RMS patients could face helps us look at the
entire issues of the patient and her family. This allows us to think ahead and act
faster than the disease. Effective communication and cooperation between the teams
is the key to success.
Advanced technology (like a closed-loop insulin pump) may make a difference. Patient
compliance is essential when trying medications like leptin and IGF1 to improve insulin
sensitivity and reduce hyperinsulinemia. Successful management of insulin resistance
type A requires considering the patient's and family's situation. Further research
on the management of RSM patients is required.
