Rabson-mendenhall syndrome.

Rabson-Mendenhall syndrome (RMS) is a rare genetic disorder characterized by growth retardation, dysmorphisms, lack of subcutaneous fat, acanthosis nigricans, enlarged genitalia, hirsutism, dysplastic dentition, coarse facial features, abnormal glucose homeostasis, hyperinsulinemia and pineal hyperplasia. Herein, we describe a 13-year-old girl with physical features of RMS who presented to us on account of acanthosis nigricans.

What was known?

A manifestation of severe insulin resistance, Rabson-Mendenhall syndrome presents with florid metabolic, cutaneous and systemic features thereby revealing the manifold effects of insulin on metabolism.

Introduction

First described by Rabson and Mendenhall in 1956 in three siblings presenting with dental and skin abnormalities, abdominal distension, coarse facies, early dentition, hirsutism, phallic enlargement and pineal hyperplasia, Rabson-Mendenhall syndrome (RMS) is a rare insulin resistance syndrome of unknown prevalence. It is inherited as autosomal recessive trait with variable expressivity. There is paradoxical fasting hypoglycemia and post-prandial hyperglycemia initially in life, followed by constant hyperglycemia (by 4 years of age) and constant ketoacidosis by 6 years of age. Although insulin levels are extremely elevated initially and then decrease with age, they remain higher than normal.[12]

This case is being presented to highlight the wide spectrum of manifestations of this syndrome for its rarity and relative paucity of reports in dermatological literature.

Case Report

A 13-year-old girl presented with complaints of progressively increasing blackish discoloration of the folds of the body [Figure 1], polydipsia and polyuria. The girl was first in birth order, born of a consanguinous marriage after a full-term uneventful pregnancy. Two of her siblings had died in the perinatal period. On examination, the girl was found to have a coarse facies with a broad nose, prognathism and a fissured tongue. The teeth were irregular and crowded [Figure 2]. The abdomen was distended and loss of subcutaneous fat was visible [Figure 3]. Generalized hypertrichosis was noticed.

Figure 1

Acanthosis nigricans seen extending beyond the neck

Figure 2

Fissured tongue with overcrowding of teeth

Figure 3

Abdominal distension with loss of subcutaneous fat

Extensive acanthosis nigricans was conspicuous on the neck extending upto the sides of the face and the chest, the axillae, ante-cubital fossae, lower abdomen, groins, thighs, popliteal fossae and dorsum of feet proximally. The girl had a normal physical and mental development with Tanner's stage 2 breast axillary and pubic hair development. Examination of the genitals revealed phallic enlargement and clitoromegaly [Figure 4]. Examination of the nails was unremarkable. Examination of the scalp revealed premature graying of hair which has not thus far been reported in any series [Figure 5].

Figure 4

Clitoromegaly

Figure 5

Premature graying of hair

Systemic examination was not contributory. Routine blood counts, kidney and liver function tests were within normal limits. Routine urine analysis revealed a glycosuria of 2%. Fasting, postprandial and random blood sugars were 172 mg%, 708 mg%, and 387 mg%, respectively. The patients serum insulin levels were 530 μU/ml (normal range 2-20 μU/ml) and C-peptide levels were 46 ng/ml (normal range 0.8-3.5 ng/ml).

On the basis of these observations a diagnosis of RMS was made.

Discussion

RMS is a rare autosomal disorder characterized by severe insulin resistance, affecting males and females in equal number. The patients usually survive upto 5-15 years of age. Severe insulin resistance is caused either by genetic defects of the insulin receptor gene (Type A) or by the presence of circulating autoantibodies that disrupt the normal functions of the insulin receptor (type B). The primary defect in RMS appears to be in the insulin receptors. The gene map locus is 19p 13.2.[3]

The symptoms of RMS may include intrauterine and postnatal growth retardation, dysmorphisms, nail, teeth, and skin abnormalities. The patients characteristically develop fasting hypoglycemia and postprandial hyperglycemia followed by, as the disease progresses, persistent hyperglycemia which eventually leads to persistent ketoacidosis.[45]

Our patient had features of persistent hyperglycemia. The paradoxical fasting hypoglycemia is caused by inappropriately elevated insulin levels at the time of fasting, due to excessive production of insulin by the pancreas, coupled with the prolonged half-life of the hormone.[4]

In individuals with RMS, the body may attempt to compensate for insulin resistance by increasing insulin secretion, which may lead to excessive insulin levels in the blood (hyperinsulinemia). Hyperinsulinemia may result in certain features associated with RMS such as acanthosis nigricans, hypertrichosis, and polycystic ovaries. As RMS progresses, insulin levels decrease and are no longer capable of suppressing hepatic glucose production and release resulting in constant hyperglycemia. When insulin levels decrease further, their capacity to suppress fatty acid oxidation is compromised, and constant ketoacidosis ensues.[6] The progressive decline in insulin levels mimics what is observed in patients with type 2 diabetes though at a faster rate. The changes observed in RMS in a few years require decades in type 2 diabetes. Even in RMS there is variability in the rate of decline in insulin levels.[456]

The mutations in the insulin receptor gene cause a spectrum of inherited insulin-resistance syndromes ranging from severe leprechaunism to Type A insulin resistance (usually evident after puberty); RMS has an intermediate phenotype with survival beyond one year but death usually before puberty.[4567] Leprechaunism (Donohue syndrome) and RMS both are autosomal recessive conditions with abnormal alleles for insulin receptors. Most of the clinical features are similar in the two conditions. Affected infants may have distinctive abnormalities of the head and face (craniofacial) region, low birth weight, skin abnormalities and abnormal enlargement of the breast and clitoris in females and the penis in males.[8] However, infants with leprechaunism do not survive beyond the first year of life.[9] They present with more severe manifestations and do not develop ketoacidosis, their major problem being fasting hypoglycemia. RMS differs from leprechaunism by being less severe, and by the presence of premature and dysplastic dentition, coarse facial features, gingival hyperplasia, pineal hyperplasia, and survival beyond 1 year of age.[46789]

Leprechaunism and RMS should be considered as a continuous spectrum, in which the specific mutation and the degree of impairment of insulin action predict the survival, rather than the types of the syndrome. Another disorder, acanthosis nigricans with insulin resistance type A, also caused by mutations in the insulin receptor gene, is a rare form of acanthosis nigricans characterized by skin abnormalities, insulin resistance, hyperinsulinemia, potential development of diabetes; multiple cysts on the ovaries, increased androgens levels and/or hirsutism represents a milder phenotype.[7]

Lipodystrophies were also considered in the differential diagnosis. They are a group of rare metabolic disorders characterized by abnormalities in adipose tissue associated with total or partial loss of body fat, abnormalities of carbohydrate and lipid metabolism, severe insulin resistance and immune system dysfunction. Apart from differences in physical appearance, high triglyceride levels and low HDL levels are observed in patients with lipodystrophy. Patients with RMS despite having high levels of insulin do not show raised triglyceride levels.

There is no specific treatment for individuals with RMS. The treatment is generally supportive. The goal is to maintain blood glucose levels as constant as possible with the use of frequent or continuous feeds and complex carbohydrates. Insulin is not effective at normal doses, minimal effects on glucose levels can be seen with extra large doses of insulin (up to 9 U/kg per hour). The treatment of the disorder is directed toward the specific symptoms. Affected individuals may receive high doses of insulin or insulin sensitizers, but in most cases this therapy ultimately proves unsuccessful. Treatment may require the coordinated efforts of a team of specialists including pediatricians, surgeons, dental specialists and other health care professionals. High doses of recombinant insulin-like growth factor I (rhIGF-I) have been used to treat individuals with ketoacidosis and it has demonstrated improvement in some affected individuals. The administration of recombinant methionyl human leptin (r-metHuLeptin) has also been shown to improve fasting hyperglycemia, hyperinsulinemia, glucose, and insulin tolerance in RMS.[7] Biguanides, which may lead to an increased number of insulin receptors have also been tried with variable success.[89101112]

Conclusions

Rabson-Mendenhall syndrome is a genetic disorder, the treatment of which still remains far from satisfactory. Newer research targeting gene therapy may help improve the clinical outcome in these patients.

What is new?

Despite various treatment modalities, the prognosis of patients with Rabson Mendehall Syndrome remains far from satisfactory. Recombinant IGF-1 and subcutaneous leptin therapy, which promise good results, have been tried only in a few cases. Further studies need to be undertaken to understand their role in this rare genetic disorder