Turner syndrome with primary myelofibrosis,cirrhosis and ovarian cystic mass:A case report

lNTRODUCTlON

Turner syndrome(TS)is the most common X chromosome monosomy,affecting one in 2500 live births among females[1].The clinical features of TS include a short stature,gonadal failure,cubitus valgus,micrognathia,short neck,limb edema,webbed neck or cystic hygroma,low posterior hairline,short fourth metacarpal,and multiple naev[2-4].Patients with TS suffer progressive cardiovascular,metabolic,and autoimmune comorbidities,as well as dysgerminoma[5,6].TS with leukemia is a complicated clinical condition.Although the correlation between TS and hematologic malignancies remains unclear,several cases of TS with acute myelocytic leukemia[1]or large granular lymphocyte leukemia[7]have been reported.The incidence of chronic myeloid proliferative neoplasm in TS patients is rare,especially coinciding with cirrhotic portal hypertension and gynecologic disease.We report a case of TS with primary myelofibrosis(PMF),cirrhosis,and an ovarian cystic mass.

CASE PRESENTATlON

Chief complaints

In April 2020,a 20-year-old woman with fatigue and shortness of breath hospitalized at our clinic.

History of present illness

Six months prior,she had an abnormal menstrual period and was admitted to another hospital.She had elevated white blood cell(WBC)counts,anemia,and thrombocytopenia.She was diagnosed with PMF by bone marrow aspiration.Biopsy exhibited myelofibrosis(MF)grade 2.Since then,she has been treated with ruxolitinib(10 mg,per oral,twice daily)without regular follow-up.Magnetic resonance and enhancement revealed cirrhosis,splenomegaly,and a large cystic mass in the right ovary.However,no further details regarding cirrhosis and the cystic mass obtained.

History of past illness

The patient had no significant medical history.

From that day forth2, the girl began a new habit. Her cell phone never shuts down at night. Because she was afraid that she might not be able to hear the phone ring in her sleep, she tried to stay very alert3. As days passed, she became thinner and thinner. Slowly, a gap4 began to form between them.

Personal and family history

The patient had no remarkable personal or family history.The rest of the patient’s relatives are very healthy and tall.

Time virtually16 flies like a rocket; the train life was over in a flash. We came back with the good memory and deep friendship (there we knew each other well and became good friends). In our imagination, some of us burst out tears when leaving but not me (am I very cruel? Hehe). I know the whole new life is welcoming us to go back. What we can do is just putting the memory away.

Physical examination

On admission,the patient presented with anemia and abdominal swelling,similar to that of a pregnant woman.On physical examination,she was 148 cm tall,which was not consistent with the other family members.She weighed 45 kg and had a body mass index of 20.5.She had a webbed neck,low posterior hairline,epicanthus,and sixth toe on her right foot.She was clinically diagnosed with TS.

King Cloverleaf and Queen Frivola had but one child, and this Princess had from her very babyhood been so beautiful, that by the time she was four years old the Queen was desperately2 jealous of her, and so fearful that when she was grown up she would be more admired than herself, that she resolved to keep her hidden away out of sight

Laboratory examinations

The chromosome analysis of the bone marrow cells revealed 45,X/46,XX,confirming the diagnosis of TS[8].The peripheral blood cell count revealed a WBC count of 1.93 × 10/L,hemoglobin(Hb)count of 38 g/L,and platelet(PLT)count of 84 × 10/L.Bone marrow aspiration indicated the coexistence of megakaryocytic emperipolesis and immature megakaryocyte cluster formation,while biopsy exhibited MF grade 1.Gene mutation testing revealedandmutations.

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Laboratory tests reported a remarkably elevated glutamic oxalacetic transaminase of 77.95 U/L(normal: 13-35 U/L),and glutamic-pyruvic transaminase of 84.1 U/L(normal: 7-40 U/L),while cholesterol and glucose levels were in the normal range(Table 1).The hepatitis panel,human immunodeficiency virus test,and autoantibody screening results were negative(Table 2).The carbohydrate antigen level of CA125 was 78.5 U/mL(normal ＜ 35 U/mL).Gonadal hormones such as serum β-HCG and luteinizing hormone were within the normal ranges(Table 1).However,liver fibrosis markers were significantly elevated(Table 3),the significantly decreased amount of ferritin,normal ceruloplasmin and ophthalmic testing without ophthalmic signs(Kayser-Fleischer rings)allowed us to exclude the diagnosis of hemochromatosis and Wilson’s disease.No structural defects observed in the heart and major vessels on echocardiography.Abdomen ultrasound showed a huge cystic mass measured as 30 mm × 148 mm on the right ovary,which is considered as a serous cystadenoma.

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Abdominal computed tomography(CT)revealed splenomegaly(114 mm × 100 mm × 163 mm;Figure 1A),cirrhosis,and portal hypertension.On the CT scan,an ovarian cystic mass,measuring 236 mm × 143 mm × 255 mm(Figure 2A)was detected on the right side.

Imaging examinations

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MULTlDlSClPLlNARY EXPERT CONSULTATlON

Cai-Sheng Xu,MD,Chief Doctor,Professor,Department of Gynaecology

Our patient had intermittent hematemesis and melena due to portal hypertension,resulting in a decreased platelet count.Cryptogenic cirrhosis with upper gastrointestinal bleeding has been reported in TS patients[11].The reduction of intrahepatic resistance by a transjugular intrahepatic portosystemic shunt is a viable option in patients who were not successfully treated by conservative medical treatment[21].

Jian-Lin Fang,MD,Chief Doctor,Professor,Department of Invasive Technology

“A large ovarian cystic mass has been found;removal of the ovarian cystic mass may easily lead to disorder of the internal circulation.Insufficient return blood can lead to cardiac arrest at any time,which can be life-threatening.”

Bao-An Wu,MD,Chief Doctor,Professor,Department of Gastrointestinal Surgery

“The patient is diagnosed with cirrhosis with portal hypertension and splenomegaly.During the surgery,because a change in abdominal pressure can cause venous bleeding in the liver,splenectomy and splenic embolization should be considered to reduce portal pressure prior to surgery.”

FlNAL DlAGNOSlS

Six months later,the patient experienced hematemesis and melena for 3 d and was admitted to our hospital.Severe esophageal and gastric fundus varices were observed on gastroscopy.An abdominal CT scan showed splenomegaly(100 mm × 76 mm × 213 mm;Figure 1B)and an ovarian cystic mass with the same size(Figure 2B)as before.Peripheral blood cell count revealed a WBC of 2.59 × 10/L,Hb of 47g/L,and PLT count of 41 × 10/L.Ruxolitinib was interrupted.Antacids and hemostatic agents were administered to control the bleeding.At present,the patient has remained well with moderate anemia and thrombocytopenia.

TREATMENT

Ruxolitinib was intermittently used based on the blood platelet count.The recommended starting dose is 5mg or 10 mg twice daily,depending on platelet counts(≥ 50 to ＜ 75 × 10/L,75-100 × 10/L,respectively)regardless of Hb level.When the blood platelet count ＜ 50 × 10/L,ruxolitinib use is recommended to cease.

During her hospitalization,the patient had menorrhagia.Triptorelin(3.75 mg,monthly)was injected to control the abnormal bleeding.Due to the splenomegaly and ovarian cystic mass,she had abdominal swelling similar to that of a pregnant woman and suffered from low self-esteem.A multidisciplinary team was formed to discuss the possibility of surgical removal of the ovarian cystic mass.Due to the high risk of sudden cardiac arrest and uncontrollable bleeding after tumor removal,surgery was not performed.

OUTCOME AND FOLLOW-UP

TS,PMF withandmutations,cirrhosis,and ovarian cystic mass were diagnosed.

DlSCUSSlON

TS patients have an increased morbidity and mortality due to coronary diseases,congenital malformations,and endocrine diseases[9].Cases of TS with hematologic malignancies are rare,with few reported cases.Down syndrome is closely related to leukemia because of trisomy 21[8,10].However,the mechanisms behind the relationship between TS and hematologic malignancies remain unknown.We report the first case of TS with PMF,cirrhosis,and an ovarian cystic mass.

This patient was a 20-year-old female who presented with extensive splenomegaly and cirrhosis.Although liver and ovarian failure are typical features of TS,cirrhosis and portal hypertension rarelyoccur,especially in young patients[11].However,the incidence of cirrhosis is reportedly increased by 6-fold in TS patients[12].For this patient,low levels of ferritin and no iron overload in the liver and/or spleen on magnetic resonance imaging of the liver could exclude the diagnosis of hereditary hemochromatosis[13].Wilson’s disease was also excluded because of normal range of ceruloplasmin and absence of ophthalmic signs(Kayser-Fleischer rings)[14].Also alcoholic liver disease,non-alcoholic fatty liver disease and infective forms of hepatitis was excluded.However,a thorough genetic examination is needed to verify that the patient has no genetic disorders related to liver cirrhosis such as hereditary hemochromatosis,Wilson’s disease and alpha-1 antitrypsin deficiency.During her hospital stay,the PLT count was sometimes less than 50 × 10/L and transfusion effect is poor,so liver biopsy was not considered.According to Roulot[15],the liver abnormalities in TS patients are mainly caused by congenital vascular disorders.Considering the unknown origin of cirrhosis,genetic disease detection or liver biopsy is needed when it is permitted.

The patient was diagnosed with PMF withandmutations by bone marrow aspiration and next-generation amplicon sequencing.She was treated with ruxolitinib(5-10 mg twice daily),depending on platelet counts(≥ 50 to ＜ 75 × 10/L,75-100 × 10/L,respectively)regardless of Hb level.Though it is well recognized that low red blood cell counts are observed as side effects of ruxolitinib,Cervantes[16]and Verstovsek[17]believe that it is unnecessary to delay or withhold ruxolitinib because of co-existent or treatment related anemia.Ruxolitinib is discontinued when the blood platelet count ＜ 50 × 10/L.Most of patients with myeloproliferative neoplasms can achieve a ≥ 50% reduction in palpable spleen length at any time during the treatment with ruxolitinib[16].The level of myelofibrosis was reduced after ruxolitinib treatment,however,significant splenomegaly was observed in this patient after 48 wk treatment with ruxolitinib,hypersplenism may be the main cause of pancytopenia instead of the side effect of ruxolitinib.Therefore,we consider the blood routine does not represent his true level,we make treatment plan of ruxolitinib which is correlate with Roulot[15].

Xu LW was responsible for the clinical management of the patient and writing the paper;Tao HF treated the patient and revised the manuscript;Su YZ contributed to the follow-up of the patient;all authors contributed to the article and approved the submitted version.

“The patient is diagnosed with TS,PMF,cirrhosis and large ovarian cystic mass.At present,she is facing the problem that her uterus is currently bleeding irregularly and the large ovarian cystic mass make her life inconvenient.Removal of the uterus and cystic mass is urgently needed,however,portal hypertension and splenomegaly make it extremely difficult,owing to the risk of excessive bleeding and unstable circulation.”

An ovarian cystic mass was discovered by CT scan.It maintained the same size for 6 mo,and there was no apparent tumor infiltration.Although pathologic examination was not conducted,the mass was likely a benign ovarian tumor.Mukerji[22].established a close relationship between TS and germ cell tumors.Moreover,gonadoblastomas commonly occur during the second decade of life,which is consistent with the age of our patient.Gonadoblastoma is a pre-malignant neoplasm with a germ cell component,liable to malignant transformation into invasive dysgerminoma.Further pathological examination should be performed in our patient to determine the necessity of gonadectomy for preventing cancer.

CONCLUSlON

Our case was limited because no pathological data of the ovarian cystic mass and liver were obtained due to the risk of surgery.To our knowledge,this is the first case of TS accompanied by MF.More research is needed to understand the concurrence of TS and leukemia,as well as other complications.Further studies on cirrhosis and PMF are necessary to clarify the pathological and physical changes in hepatosplenomegaly.

ACKNOWLEDGEMENTS

The authors thank all the investigators involved in this study,including the physicians,nurses,pathologists and laboratory technicians.

FOOTNOTES

Whether the mutations found in this patient,such as those involvingand/or,have prognostic importance on the treatment of PMF is unknown.In essential thrombocythemia patients,mutation inwas found to be an additional negative prognostic factor[18],which has not been clearly demonstrated in PMF.Though it is recognized thatis associated with higher risk of fibrotic progression in essential thrombocythemia[19],definitive conclusions regarding the impact ofandmutations on prognosis or other pathological changes are difficult due to the fact that less than 10% of patients with PMF harbor alternations in thegene[20]and the rarity ofmutations in PMF patients.

Informed written consent was obtained from the patient for publication of this report and any accompanying images.

The authors declare that they have no conflict of interest.

The authors have read the CARE Checklist(2016),and the manuscript was prepared and revised according to the CARE Checklist(2016).

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers.It is distributed in accordance with the Creative Commons Attribution NonCommercial(CC BYNC 4.0)license,which permits others to distribute,remix,adapt,build upon this work non-commercially,and license their derivative works on different terms,provided the original work is properly cited and the use is noncommercial.See: https://creativecommons.org/Licenses/by-nc/4.0/

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Oh, my gosh! Papa said, clapping a hand to his forehead. I ve been so stupid! I just thought she d want to be a champion swimmer because she s so good at it.

Lin-Wei Xu 0000-0002-4012-0424;Yong-Zhong Su 0000-0002-7629-5760;Hong-Fang Tao 0000-0002-5014-9300.

Guo XR

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As a girl, all the fresh things can attract their eyes. Yeah. This time curiosity17 can t kill a cat. When coming back, the first thing we want to do is chatting. Talking about all the things in high school. From the talk, I know all the dorm mates are ambitious and they are eager to achieve their own goals. In fact, all the days are almost the same, we didn t know if there were any fresh things in college life except making boyfriend (Just joking here, of course, we have never been so simply). Everyday, except chatting just chatting, maybe some study for the scholarship. And the term passed quickly. You must be strange isn t there any contradiction18 among you and your dorm mates? It s true that we do have. But it won t last several days. (Very happy, isn t it?)

Guo XR