FAMILIAL ATYPICAL HEMOLYTIC UREMIC SYNDROME
WITH POSITIVE p.S1191L (c.3572C>T) MUTATION ON
THE CFH GENE: A SINGLE-CENTER EXPERIENCE
Ersoy Dursun F1,*, Yesil G2, Sasak G3, Dursin H4
*Corresponding Author: Dr. Fadime Ersoy Dursun, Hematoloji Bilim Dalı, Istanbul Medeniyet Universitesi
Tıp Fakultesi, Dr. Erkin Cad. No. 6, 34722 Kadıköy, Istanbul, Turkiye. Tel.: +90-536-838-5101.
Fax: +90-216-606-5210. E-mail: drfadimeersoy@yahoo.com.tr
page: 81
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DISCUSSION
This study reports scanned results of a family who
presented at our center. In six of 13 family members, the
p.S1191L mutation on the CFH gene was heterozygous.
While three of these six family members (AT, CT and MT)
had clinical and laboratory findings of the p.S1191L mutation
on the CFH gene, two members (DT, NT and MUT)
did not. There was no gene mutation or aHUS finding in
the other seven family members. However, a total of six
siblings of our index patient died. It was found that the
cause of death of three was CRF, and the cause of death
of the other three siblings was not known. In addition, one
uncle of our index patient died from CRF. These findings
show that the phenotype and penetrance of the CFH gene
mutations differ from person to person.
Some cases with the CFH: p.S1191L gene mutation
have been reported in the literature [21-23]. In the first of
these articles, it was reported that a gene mutation [c.3572
(C>T), Ser1191Leu] was detected in a 12-year-old female
patient. A renal transplant was performed on this patient
after she developed chronic renal failure. Recurrence of
aHUS has been reported after renal transplantation. The
same gene mutation was detected in the younger twin
sisters of this girl, but clinical and laboratory findings of
aHUS did not develop [21]. The history of these cases is
very similar to our cases. In another publication [24], a
7-month-old female baby who presented with aHUS associated
with combined de novo CFH mutations (p.s1191L
and V1197A), whose relapses could be treated with plasmapheresis
at that time, but no information on ECZ treatment
was provided. No results about the deaths of a mother
and daughter were reported in another publication [16].
Therefore, it can be concluded that the appearance of this
mutation is discouraging. However, as shown in our index
case, positive results can be obtained with ECZ therapy.
The significance of our study is that there were cases
who are affected and not affected by the gene detected in
the same family. This reflects the penetrance of the gene
mutation in the literature. Another important result is the
demonstration of the effectiveness of the ECZ therapy.
In aHUS, patients may be identified as familial or
sporadic cases. In inherited cases, genetic mutations in
CFH, CFI, C3 convertases, C3 and factor B, thrombomodulin,
CD46 and MCP can lead to complement-related
HUS. Other factors such as deficiency of metalloprotease
activity that cleaves von Willebrand factor (VWF-CP
or ADAMTS-13), CFI deficiency, and auto antibodies
against CFH may also cause aHUS [25]. These mutations
in complement components or regulatory proteins plays an
important role in the pathogenesis of aHUS in 50.0-60.0%
of patients. These mutations cause mis regulation of the complementary alternative pathway in the endothelium,
triggering attacks of thrombotic microangiopathy in the
renal microvasculature and other vital organs [26-28]. A
gene mutation in CFH (p.S1191L mutation in the CFH
gene) was found in the studied family. This gene encodes
factor H, which competitively binds to C3b to inhibit the
production of C3 convertase, accelerates decay of C3 convertase,
and acts as a cofactor of factor I to cleave C3b [29].
The CFH mutations, chiefly affecting the C-terminal, account
for 15.0-20.0% of mutations in patients with aHUS.
Antibodies against FH attach chiefly to the C-terminal,
decrease FH binding to C3b, and increase alternative
pathway-dependent cell lysis [30].
The history of CRF and renal transplantation resulting
in rejection in two patients was also associated with
aHUS that might have occurred as a result of a mutation in
this gene. No pathologies were detected in the other three
family members with gene mutation, including the mother
and a 2-year-old child. Therefore, the question arises as
to whether factors such as female gender, not having experienced
a triggering event, and young age could serve
as protective features in the disease. The absence of any
pathological findings in the third family member may have
resulted from a mechanism that we cannot explain. There
exist studies describing this phenomenon in the literature.
Despite heterozygous pathogenic variants in complement
genes often identified in diseased and healthy parents,
the disease is often sporadic, which indicates that genetic
mutations give rise to sensitivity, but they do not cause
disease [31]. The disease occurred in approximately 50.0%
of the family members affected by the gene mutation by
the time they reach 45 [32]. Arjona et al. [33] found that,
in addition to the complement pathogenic mutation, carrying
the MCPggaac haplotype or both the MCPggaac and
the CFH-H3 haplotypes, raises the aHUS penetrance to
9.4 and 14.5%, respectively, by the age of 35 years, and
the maximum aHUS penetrance to 15.0% (48 years) and
18.8% (37 years). In studies conducted on this subject,
the results of genetic mutations were examined. These
studies showed that the C3 mutation induces increased C3
convertase formation, thereby enhancing the alternative
pathway [34]. The homozygous IVS-II+2 (T>G) mutation
on the CD46 gene may be clinically silent, especially in
childhood, similar to the heterozygous mutation [35]. In
this study, the presence of an aHUS-related progressive
decline in renal function, microangiopathic hemolytic anemia,
and thrombocytopenia in one person in the family
was attributed to the heterozygous p.S1191L mutation on
the CFH gene. This well-established feature of the disease
has also been confirmed by our study. In the present study,
three (50.0%) of six patients with the heterozygous gene
mutation developed the disease.
In addition to our index patient, the CFH: p.S1191L
mutation was heterozygous in his two siblings with CRF.
These two patients had a kidney transplant history, but
both developed acute rejections shortly after their transplant
surgeries. Both of these patients still receive regular
hemodialysis treatment 3 days a week. Other laboratory
findings are normal in these patients, indicating that no
triggering events of aHUS have so far occurred in their
lives. The diagnosis of aHUS in his siblings and the detection
of mutations on the CFH gene in the same gene
with his siblings suggest that the presence of CRF and
rejection after renal transplant in these patients might be
associated with their aHUS, but they are not yet in the
period of aHUS episodes.
In the treatment of atypical HUS, ECZ, a monoclonal
antibody that inhibits complement protein C5, has been
demonstrated to be an effective treatment option. In recent
years, multicenter studies have shown that ECZ therapy
rapidly improves the platelet count and renal functions in
most patients after the first dose, eliminating the need for
dialysis and plasma treatment. Eculizumab has been reported
to be a fast, effective, and life-saving option in treating
aHUS [36-39]. In the present study, our index patient
with the CFH: p.S1191L mutation was treated with ECZ,
and he had a good response and survived. In a clinical trial
of ECZ, a shorter interval between the clinical manifestation
of aHUS and treatment initiation was associated with
greater improvement in the estimated glomerular filtration
rate [40]. Accordingly, we administered ECZ therapy to
our index patient following plasmapheresis after the first
admission. After ECZ treatment, the patient improved and
his clinical and laboratory findings and returned to normal.
Limitations and Strengths. First of all, in our study,
we should have performed genetic analysis on more family
members, and secondly, we had to determine the causes
of death of the deceased individuals of the family more
clearly, but we could not.
Conclusions. This study identified six people who
were heterozygous for the p.S1191L mutation on the CFH
gene in a family of 13 individuals who were genetically
screened. While three of these cases showed no aHUS findings,
we detected aHUS and CRF in the other three cases,
which indicated that the genes affect the disease penetrance
by about 50.0%. A more thorough screening of all family
relatives could detect a higher incidence of the gene in this
family. Failure to diagnose aHUS as a cause of CRF in
two individuals of this family during previous follow-up
appointments and performing renal transplants before ECZ
therapy prophylaxis may have caused renal transplant rejection
in both patients. Therefore, this study has revealed
that these family members should be closely monitored for
early signs and symptoms of aHUS. The administration of ECZ is recommended for genetic variation carriers with a
familial history or multiple relapses of aHUS. The availability
of ECZ has fundamentally improved the outlook
for patients with aHUS. This prospective study confirmed
that ECZ inhibits complement-mediated thrombotic microangiopathy.
Prevention of hemolysis and renal function
improvement during ECZ therapy, without the need for
plasma exchange/plasma infusion, represents an important
clinical benefit. The ongoing extension treatment phase
and a global aHUS registry study will provide further
insights regarding the long-term use of ECZ in patients
with familial aHUS.
Acknowledgments. This study, titled “Familial
Atypical Hemolytic Uremic Syndrome with Positive
pS1191L (c.3572C>T) Mutation in CFH A Single-
Center Experience” was published as a pre-print in the
BMC Nephrology journal (Fadime Ersoy Dursun et al.).
However, BMC Nephrology rejected our article at the last
stage. Moreover, we would like to thank all the participants
in the study.
Declaration of Interest: The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
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