|Year : 2015 | Volume
| Issue : 4 | Page : 230-233
Novel FSH receptor mutation in a case of spontaneous ovarian hyperstimulation syndrome with successful pregnancy outcome
Anahita R Chauhan1, Madhva Prasad1, Sumit Chamariya1, Swati Achrekar2, Smita D Mahale2, Kartik Mittal3
1 Department of Obstetrics and Gynecology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, Maharashtra, India
2 Division of Structural Biology, National Institute for Research in Reproductive Health, Parel, Mumbai, Maharashtra, India
3 Department of Radiodiagnosis, Seth GS Medical College and KEM Hospital, Parel, Mumbai, Maharashtra, India
|Date of Submission||30-Jun-2015|
|Date of Decision||25-Sep-2015|
|Date of Acceptance||28-Oct-2015|
|Date of Web Publication||25-Nov-2015|
Anahita R Chauhan
Department of Obstetrics and Gynecology, Seth GS Medical College and KEM Hospital, Acharya Donde Marg, Parel, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
| Abstract|| |
The objective is to study the FSH receptor (FSHR) for mutations in a case of spontaneous ovarian hyperstimulation syndrome (sOHSS). This is a single case study and it examined patient who presented with spontaneous critical OHSS in early pregnancy and had successful good obstetric outcome. Intervention of this study was analysis of blood for genetic analysis of FSHR postdelivery. The main outcome measure noted was FSHR mutation. The study resulted in a novel, here though unreported, heterozygous mutation in FSHR gene at nucleotide position 1346 (AC 1346 T to AAT) in exon 10 yielding a threonine to asparagine (Thr 449 Asn) substitution in the transmembrane domain helix 3 of the FSHR. To conclude FSHR gene analysis can add to our understanding of sOHSS.
Keywords: FSH receptor genetic analysis, FSHR mutation, spontaneous ovarian hyperstimulation syndrome
|How to cite this article:|
Chauhan AR, Prasad M, Chamariya S, Achrekar S, Mahale SD, Mittal K. Novel FSH receptor mutation in a case of spontaneous ovarian hyperstimulation syndrome with successful pregnancy outcome. J Hum Reprod Sci 2015;8:230-3
|How to cite this URL:|
Chauhan AR, Prasad M, Chamariya S, Achrekar S, Mahale SD, Mittal K. Novel FSH receptor mutation in a case of spontaneous ovarian hyperstimulation syndrome with successful pregnancy outcome. J Hum Reprod Sci [serial online] 2015 [cited 2020 Oct 22];8:230-3. Available from: https://www.jhrsonline.org/text.asp?2015/8/4/230/170410
| Introduction|| |
Spontaneous ovarian hyperstimulation syndrome (sOHSS) is now a recognized entity, defined as OHSS appearing in patients with no history of stimulatory infertility treatment. OHSS, which otherwise may occur in normal pregnancies (Type I OHSS), is now reported to be associated with mutated FSH receptor (FSHR) gene, which may lead to recurrent sOHSS in patients presenting the mutations. Type II is secondary to high levels of human chorionic gonadotropin (hCG), while Type III coexists with hypothyroidism. , Very few cases have been reported in literature. 
Reported here is a case of sOHSS with a novel FSHR gene mutation.
| Case report|| |
A 29-year-old female married since 1 year, primigravida with 3 months amenorrhea and ultrasonographic gestational age of 8 weeks and 5 days, presented with acute onset of abdominal distension, vulval edema and breathlessness. There was no vomiting, trauma, fever, bleeding, or spotting per vaginum. She had regular past menstrual cycles and no symptoms suggestive of renal, cardiac, or liver disorders. Ultrasonography done a few weeks prior to presentation revealed a normal intrauterine pregnancy and adnexae [Figure 1].
|Figure 1: Ultrasonography images showing normal endometrial cavity (intrauterine pregnancy) and bilateral ovaries|
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The patient was conscious, cooperative, afebrile, with no tachycardia and normotensive. Cardiovascular system examination was normal. Breath sounds were reduced on the right side. Abdominal examination revealed shiny skin, tense ascites with no guarding, rigidity, or tenderness. Vaginal examination revealed an anteverted uterus with bilateral nontender forniceal fullness. History was reconfirmed; patient had not sought any medical advice or treatment for fertility enhancement.
Blood investigations revealed hyponatremia (125 meq/l) and hypoalbuminemia (3.4 gm/dl). Hemoglobin, white blood cell count, platelet count, coagulation profile, liver enzymes, blood urea nitrogen, and serum creatinine were normal. Estradiol was elevated at 12927 pg/dl (normal range 188-2497 pg/dl). Thyroid profile and β-hCG were normal. Ultrasonography revealed a multiloculated cystic lesion of size 17 cm × 11 cm with vascularity within the wall of cystic lesion. Ascites and bilateral pleural effusion were present [Figure 2]. Features of OHSS were confirmed on magnetic resonance imaging (MRI) [Figure 3].
|Figure 2: Ultrasonography B-mode images show intrauterine fetus with multiple cysts involving both the right and left ovary. There is mild free fluid in the intra-peritoneal cavity with left pleural effusion|
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|Figure 3: T2-weighted magnetic resonance imaging pelvic coronal images show T2-hypo intense lesion in the intrauterine cavity suggestive of fetus. There are hyper intense multiple cysts seen without any mural nodule arising from both right (in right iliac fossa) and left ovary (in pouch of Douglas)|
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Vital parameters, intake-output, and abdominal girth were monitored. Additional intravenous fluids were omitted, oral fluids were encouraged, and diuretics were initially required. Hyponatremia gradually improved. In view of severe hypoalbuminemia, intravenous albumin infusion was instituted (25 g in 0.1 L solution per day for 7 days). No interventional procedure was done for ascites and pleural effusion, both of which reduced, along with the adnexal mass. Unfractionated heparin 5000 U subcutaneous injection twice daily was instituted and continued for 9 days. She was discharged after 2 weeks of inpatient stay.
The remainder of the antenatal period was uneventful. Regular ultrasonographic monitoring showed further reduction in size of adnexal mass. At 40 weeks' gestation, patient underwent cesarean section in view of nonprogress of labor and delivered a healthy male of 2.85 kg. Intraoperatively, an left ovarian simple cyst of 5 cm × 5 cm was observed, for which no intervention was done. Postoperative MRI revealed simple left ovarian cyst of 2 cm × 2 cm, right side normal and involuting uterus [Figure 4] .
|Figure 4: T2-weighted magnetic resonance imaging pelvis images 6 weeks postpartum show complete resolution of bilateral cystic lesions with a single follicular cyst in the left ovary and multiple small follicles in the right ovary|
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To investigate further, if ovarian hyperstimulation observed in this patient was due to any mutation in FSHR gene, the patient was called back after delivery. The entire exonic region of FSHR gene was screened for known/novel mutations as described earlier.  To our interest, we identified a novel heterozygous mutation in FSHR gene leading to a change at amino acid position 449 [Figure 5]. This was observed to be a transversion at nucleotide position 1346 (AC 1346 T to AAT) in exon 10 yielding a threonine to asparagine (Thr 449 Asn) substitution in the transmembrane domain helix 3 of the FSHR. The Genbank accession number for this novel mutation (T 449 N) is KP340897.
|Figure 5: (a) Electropherogram of 5'-3' strand of the exon 10 of FSHR gene, showing a wild type sequences (upper panel) of a control subject and heterozygous mutant sequence (lower panel) resulting in change of nucleotide 'C' to 'A/C' (1346 position) leading to Thr449Asn substitution identified in patient who developed spontaneous ovarian hyperstimulation syndrome during pregnancy. (b) Schematic representation of FSHR showing the position of naturally occurring novel mutationThr449Asn|
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| Discussion|| |
OHSS is usually a complication of gonadotropin stimulation during controlled ovarian stimulation protocols. The majority of OHSS cases are usually iatrogenic and are induced by exogenous hormonal therapy. The pathophysiology is one of the fluid extravasations, and the mediator appears to vascular endothelial growth factor.  With respect to the severity of clinical picture, it can be classified into:
- Grade 1: Abdominal distension and discomfort
- Grade 2: Grade 1 + nausea, vomiting, and/or diarrhea, ovaries 5-12 cm
- Grade 3: Grade 2 and ultrasonic evidence of ascites
- Grade 4: Grade 3 and/or hydrothorax or dyspnea
- Grade 5: All above with hemoconcentration, coagulation abnormalities, and diminished renal perfusion (critical OHSS).
However, it is now being recognized and slowly coming to light, in the form of individual case reports that a similar clinical picture can occur in patients, unrelated to exogenous hormone administration. ,,,,,
After a sufficient number of cases of sOHSS were reported based on the underlying primary abnormality and the triggers leading to the sOHSS, De Leener et al., have proposed a 4-group classification for this abnormality, which is shown in [Table 1].
Our patient was classified as Type 1 critical sOHSS in pregnancy and managed as per existing guidelines. Though the reports of successful completion of pregnancies complicated by sOHSS have been few, ,,, the conservative management recommended by the existing guidelines  is validated by these few successful outcomes. This is further reinforced by our case.
The understanding of the molecular basis of sOHSS is very recent, evident by the fact that the first recognition of a mutation in the FSHR gene resulting in OHSS was described very recently.  Interestingly, all the activating mutations of FSHR gene reported in women till date are associated with sOHSS leading to the activation of the receptor. ,,,,,
These mutations have been reported to cause loss of ligand binding specificity and increased response to hCG (especially in first trimester when the levels of hCG are high) resulting in hyperstimulation. 
A naturally occurring heterozygous novel mutation in FSHR gene was identified in our patient. This mutation leads to the substitution of threonine to asparagine at amino acid position 449 in FSHR. However, the functional analysis of this mutation needs to be investigated to understand the pathophysiology at the molecular level. In the wake of this finding, the patient has been counseled regarding the risk of recurrence in subsequent pregnancies.
| Conclusion|| |
At this point in time, much is yet to be understood about sOHSS and the molecular mechanisms behind it, and hence the reason of presenting this case report: A novel mutation in a condition, not fully understood.
The general gynecologist/obstetrician should have a high index of suspicion for sOHSS,  as this entity can have several implications. Genetic analysis should be considered in all patients with sOHSS to improve our understanding of this entity, paving way for an earlier recognition and improved management of this condition.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]