hereditary angioedema ( hae ) is an autosomal dominant disease characterized by recurrent episodes of potentially life - threatening angioedema ( 1 ) .
the clinical features of the disease include recurrent nonpruritic edema of skin and submucosal tissues associated with pain syndromes , nausea , vomiting , diarrhea , and life - threatening airway swellings ( 2 ) .
the fundamental abnormality in patients with hae is a mutation of the c1 inhibitor ( c1-inh ) gene , which results in the decreased synthesis of functional c1-inh antigenic protein .
two forms of hae have been described : in type i hae patients have low c1-inh antigenic protein and functional activity ( 85% of cases ) , while patients with type ii hae have normal or elevated protein but low c1-inh function ( 15% of cases ) ; in patients with a normal c1-inh gene , hae is often referred to as type iii hae . over 200 mutations
have been reported in unrelated patients ( 3,4 ) . while hae is known to be inherited in an autosomal dominant form , 25% of cases
we report a case of type i hae with a newly recognized de novo mutation of the c1-inh gene .
a 38-year - old woman presented to our emergency department with abdominal pain and nausea that had persisted for three hours .
the patient had experienced recurrent episodes of skin edema , sometimes followed by vomiting with abdominal pain , around her menstrual period for 13 years . she had no family history of hereditary diseases .
the patient 's white blood cell ( wbc ) count and platelet count were 23,200/mm and 434,000/mm , respectively .
her red blood cell count and creatinine , blood urea nitrogen , glucose , lipid , and transaminase levels were normal .
the complement studies revealed a markedly reduced c4 level of 1 mg / dl and the c1-inh level was decreased to 5.53 mg / dl ( normal 15 - 35 mg / dl ) with an activity level of < 25% ( normal 80 - 125% ) .
these laboratory data and the clinical features were compatible with a diagnosis of type i hae ; however , the patient had no family members with a history of similar episodes of recurrent edema or abdominal pain . to establish the diagnosis , we performed a dna analysis of the c1-inh gene in the patient .
we asked the center for research , education , and treatment of angioedema ( create ) to perform a gene analysis .
the patient was examined for c1-inh gene mutations by the direct sequencing of polymerase chain reaction ( pcr ) products .
the screening of each exon for small mutations was performed using a single strand conformation polymorphism ( sscp ) assay .
the presence of large mutations presences was then investigated using an multiplex ligation - dependent probe amplification ( mlpa ) assay . a direct dna sequencing analysis of the pcr products of the c1-inh gene revealed that the patient was heterozygous for a single base pair transposition of t to c at nucleotide 4429 in exon 4 ( fig .
2 ) , which led to an amino acid substitution of leu at codon 188 by pro .
the leu to pro substitution was considered to be a mutation because none of 50 healthy individuals carried this substitution ( data not shown ) . this mutation has not previously been reported . 

direct dna sequencing of the polymerase chain reaction ( pcr ) product of exon 4 from the patient identified a heterozygous , single - base substituteon ( t to c ) at nucleotide position 4429 ( arrow ) .
this mutation predicts substitution of leu ( ctg ) at codon 188 by pro ( ccg ) . 

in 1888 , william osler presented the first complete clinical description of hae , which occurred over 5 generations in one affected family ( 6 ) .
donaldson and evans noted that a biochemical abnormality , the absence of c1-inh , was responsible for hae in 1963 ( 7 ) .
it is located on chromosome 11q11-q13.1 , and consists of 8 exons , with most introns containing multiple alu repeat sequences ( 8) . an electronic database of the reported mutations is available ( 9 ) . the most common defect is a single base pair mutation .
it can occur throughout the gene and no correlation has been found between the genotype and the phenotype ( 10 ) .
our patient had recurrent episodes of skin edema and abdominal pain , low c4 titers with decreased functional and antigenic levels of c1-inh .
as this patient had no family history of angioedema , the differential diagnosis of sporadic hae and acquired angioedema was necessary .
a genetic analysis offers the clearest information for the diagnosis of such cases ( 11 ) .
the dna analysis revealed that the patient had a novel mutation of t to c at nucleotide 4429 in exon 4 of the c1-inh gene , which was consistent with a diagnosis of sporadic hae type i. the patient was therefore carrying a de novo mutation .
although we had hoped to examine her family for mutations of the c1-inh gene ( to determine whether or not the present case was sporadic ) her family members declined the examination due to their lack of symptoms . since approximately 10% of individuals carrying the defective gene
are asymptomatic , a dna analysis of the patient 's parents should be performed ( 12 ) .
however , it is sometimes misdiagnosed or overlooked , as a shown by a review of the japanese literature revealed that the mean interval between the onset of symptoms and the diagnosis of hae was 19 years ( 13 ) .
the patient had episodic edema of the extremities and facial skin and recurrent gastrointestinal attacks that occurred in association with her menstrual period .
although these were typical symptoms of hae , she had visited our hospital more than 20 times and had only been diagnosed with gastroenteritis .
we described a case of type i hae with a novel mutation of t to c at nucleotide 4429 in exon 4 of the c1-inh gene .
when a clinician suspects c1-inh deficiency , even in patients with no family history , we recommend that , when possible , physicians investigate c4 , c1 inhibitor function and c1 inhibitor antigenic protein .
 we describe a patient with hereditary angioedema type i. the patient had experienced recurrent abdominal pain around the time of her menstrual period for 13 years . 
 a laboratory examination showed reduced functional and antigenic levels of c4 and c1 inhibitor ( c1-inh ) . to establish a diagnosis 
 , we carried out a dna analysis of the patient 's c1-inh gene . 
 we determined that the patient was heterozygous for a single base pair transposition of t to c at nucleotide 4429 in exon 4 , which had not been reported in the literature . 
 as the patient had no family history of hereditary diseases , it was considered to be a de novo mutation . 
Introduction
Case Report
Discussion
The authors state that they have no Conflict of Interest (COI).