insulin resistance syndromes are a heterogeneous group of disorders with variable clinical phenotypes , associated with increased blood glucose and insulin levels .
hyperglycemia did not respond to age appropriate insulin dosage ; therefore , insulin dosage was increased , but did not lead to appropriate glycemic control .
twenty two exons of insulin receptor gene ( insr ) , on short arm of chromosome 19 , were sequenced , but no identifiable disease causing mutation was detected .
although a rare mutation within the intronic or promoter region has not been excluded in this case , further molecular studies on patients with insulin resistance syndromes associated with certain features are needed .
insulin resistance syndromes are a group of disorders with variable clinical spectrum , including extreme high insulin levels , glucose intolerance , and diabetes mellitus . various endocrine and metabolic conditions
syndromes associated with insulin resistant state , are leprechaunism or donohue 's syndrome ( abnormal facial appearance , early life growth retardation ) , rabson - mendenhall syndrome ( dental and nail abnormalities , skin lesions ) , werner syndrome ( features of premature aging ) , and alstrom syndrome ( childhood blindness , impaired hearing ) . abnormal facial appearance and dentition in association with insulin resistance resembles rabson - mendenhall syndrome ( rms ) ( omim # 262190 ) , an autosomal recessive disorder caused by mutation in the insulin receptor gene ( insr , omim*147670 ) .
growth and developmental delay , coarse facies , prognathism , gingival hypoplasia , premature and dysplastic dentition , enlarged genitalia , acanthosis nigricans , lichenified skin , onychauxis , and hypertrichosis are some of the clinical manifestations observed in these patients .
herein , we present a patient with insulin resistance syndrome with the clinical diagnosis of rms ; however , molecular analysis of the insr gene did not show any mutation .
a 10-year old girl was referred to the children 's medical center , the pediatrics center of excellence in iran , with history of poor - controlled diabetes mellitus since six years of age .
the parents of this patient were first consanguine ; the father is a 42-year old man with height of 175 cm . her mother is a 35-year old female with height of 152 cm .
the patient had a history of low birth weight ( 2200 g ) ; developed irritability at 22 days of age ; the work - up performed at that time , showed hyperammonemia .
she developed progressive abdominal protrusion ; hepatomegaly and bilateral renal microlithiasis were revealed at one year of age , based on clinical and radiological evaluation , respectively .
hyperammonemia resolved , while benzoate therapy was stopped at six years of age . at that time
all of her deciduous teeth were extracted after showing severe dental caries before the school age .
fasting blood sugar ( fbs ) was more than 350 mg / dl in repeated tests .
the diagnosis of diabetes mellitus was made ; consequently insulin treatment was started , but glycemic response was poor ; so , insulin dosage was increased gradually , without salient effect on blood glucose level .
she has been under insulin therapy ( 105 - 110 units ) and metformin ( 1000 milligram per day ) since 6 years , and 8 years old , respectively . in spite of such treatment ,
the results of recent laboratory tests were as follow : insulin > 500 mu / l ( normal range : 7 - 24
mu / l ) , ca in 24 hrs urine : 92 mg ( normal > 4 mg / kg ) , oxalate : 54 mg ( normal up to 35 mg / kg ) , hba1c : 10.5 ( normal up to 5.5 ) .
the height was 115.5 cm ( <3 percentile ) and the weight 20 kg ( <3 percentile ) at the time of admission .
her blood pressure was 105/65 mmhg ( 50 - 75 percentile ) at that time .
she had triangular face with prognathism , abnormal teeth formation , deep fissured large tongue and hair dandruff , posterior cervical and axillary acanthosis nigricans , shield chest and normal heart sounds ( fig .
the liver border was palpable 4 cm below costal margin and spleen was just palpable .
there was no evidence of hearing loss . except a delay in starting walking age ( at two years old ) ,
her psychomotor development was normal . only her growth was delayed in relation to chronologic age , but there was no evidence of muscular hypertrophy . triangular face with prognathism , abnormal teeth , deep fissured large tongue and posterior cervical acanthosis nigricans abdominal magnetic resonance imaging ( mri ) revealed large liver with increased signal density .
heart echocardiography showed tricuspid regurgitation , atreal septal defect and a hypertrophic right ventricle with appropriate systolic function .
liver function test was normal . fasting blood sugar ( fbs ) was above 350 mg / dl .
glycosylated hemoglobin a1 ( hba1c ) was 10.5% . under the clinical hypothesis of rms ,
however , only 3 homozygous single nucleotide polymorphisms ( snps ) ( c.5c > g , c.1230 g > t and c.1650 g > a ) , but no disease causing mutation was detected . indeed being suspect to pigmented hypertrichosis with insulin dependent diabetes ( phid ) , the slc29a3 [ solute carrier family 29 ( nucleoside transporter ) , member 3 ] gene
rabson - mendenhall syndrome is a rare insulin resistance disorder , which was first reported by rabson and mendenhall in 1956 in three siblings , who presented with cutaneous and skin abnormalities as well as phallic enlargement .
diabetes refractory to large doses of insulin , acanthosis nigricans and abnormal dentition are some other features of this syndrome . as rms is the only insulin resistance syndrome with dental manifestations , this clinical diagnosis was most likely for our patient .
other insulin resistance syndromes , including donohue 's syndrome , werner syndrome , and alstrom syndrome , have different clinical phenotypes which were not compatible with this presented case .
she had coarse facial appearance from birth and dysplastic , late erupting teeth , extracted before school age .
she did not respond to age appropriate insulin dosage and therefore the diagnosis of an insulin resistance syndrome was confirmed .
however , she did not have clitoromegaly , hypertrichosis , and further molecular studies did not show insr exons mutations , therefore not further substantiating the diagnosis of rms .
it should be noted that mutations in the insr gene are not limited to the rms ; and mutations within this gene are usually associated with a spectrum of inherited insulin - resistance syndromes ranging from severe leprechaunism ( donohue syndrome ) to type a insulin resistance .
analysis of 22 exons of insr gene in our patient did not show any disease causing mutation and only 3 homozygous snps ( c.5c > g , c.1230 > t and c.1650 g > a ) were identified .
although it might be possible that a very rare mutation is located within the intronic or promoter region , a new syndromic insulin resistance disorder could also be considered .
indeed , it seems that such dysmorphic phenotype is not always a valid parameter for predicting insr mutations in insulin resistance condition .
although rms seems to be the most likely clinical diagnosis for this case , it could be considered as an unusual and possibly even hitherto not yet described entity , or with rms but not caused by insr mutations .
 backgroundinsulin resistance syndromes are a heterogeneous group of disorders with variable clinical phenotypes , associated with increased blood glucose and insulin levels.case presentationherein , a 10-year old girl with abnormal face and dentition is presented 
 . she has suffered from diabetes mellitus type i since she was 6 years old . 
 hyperglycemia did not respond to age appropriate insulin dosage ; therefore , insulin dosage was increased , but did not lead to appropriate glycemic control . 
 twenty two exons of insulin receptor gene ( insr ) , on short arm of chromosome 19 , were sequenced , but no identifiable disease causing mutation was detected.conclusionalthough a rare mutation within the intronic or promoter region has not been excluded in this case , further molecular studies on patients with insulin resistance syndromes associated with certain features are needed . 
Background
Case Presentation
Conclusion
Introduction
Case Presentation
Discussion