SUBMITTED 11 SEP 22 1 REVISIONS REQ. 23 OCT 22 & 4 JAN 23; REVISIONS RECD. 14 DEC 22 & 18 JAN 23 2 ACCEPTED 6 FEB 23 3 ONLINE-FIRST: FEBRUARY 2023 4 DOI: https://doi.org/10.18295/squmj.1.2023.012 5 6 A Rare Case of Lung Hypoplasia, Cardiac Anomalies and Ovarian 7 Tumour in a Patient with MRKH Syndrome 8 Pratap Upadhya,1 Arpitha A.,2 *Sivaselvi C.,1 Dasari Papa,2 Vignesh K.1 9 10 Departments of 1Pulmonary Medicine and 2Obstetrics and Gynaecology, Jawaharlal Institute 11 of Postgraduate Medical Education & Research, Puducherry, India. 12 *Corresponding Author’s e-mail: Sivaselvisaran33@gmail.com 13 14 Abstract 15 Hypoplasia of the lung is an uncommon congenital abnormality of the respiratory system in 16 contrast to Pulmonary agenesis. Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is the 17 congenital absence of the upper two-thirds of the vagina and uterus with normal secondary 18 sexual characteristics, ovary, and normal karyotype. Here we describe a case of left lung 19 hypoplasia and congenital cardiac malformations with MRKH syndrome and Leiomyoma of 20 the ovary. A 31-year-old female presented with cough with expectoration, left side chest pain 21 and breathlessness for four years to Jawaharlal Institute of Postgraduate Medical Education 22 and Research (JIPMER). She was evaluated for amenorrhea and diagnosed as MRKH 23 syndrome and the patient underwent right side oophorectomy for right ovarian torsion with a 24 tumour. Computed Tomography Pulmonary Angiogram (CTPA) and fiberoptic endoscopy 25 were suggestive of left lung hypoplasia, and the patient was advised symptomatic treatment 26 for lung hypoplasia and planned for vaginoplasty. 27 Keywords: Pulmonary hypoplasia, Infertility, Mullerian aplasia, congenital bronchiectasis, 28 Left-sided superior vena cava, ovarian Leiomyoma. 29 30 Introduction 31 Pulmonary Hypoplasia is a developmental lung anomaly characterized by a decrease in the 32 number of airway, alveoli and lung cells leading to a net reduction in the lung's size and 33 weight. It can be either unilateral or bilateral.1 Estimated prevalence of pulmonary 34 Hypoplasia is 1-2 per 12000 births although the exact prevalence is not well known.2 35 Pulmonary Hypoplasia usually presents with other associated cardiovascular,gastrointestinal, 36 and genitourinary tract anomalies. The onset of Clinical manifestations usually depends upon 37 the degree of Hypoplasia.3 38 39 Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a rare congenital problem in women 40 and it is characterized by failure of the appropriate development of the uterus and the vagina 41 with normal external genitalia and normal ovarian function. They develop secondary sexual 42 characteristics during puberty (e.g., breast development and pubic hair) but present with 43 primary amenorrhea. The estimated incidence of Mayer-Rokitansky-Küster-Hauser syndrome 44 (MRKH syndrome) is 1 in 4500 female births.3 Most cases are sporadic. Autosomal 45 dominance with an incomplete degree of penetrance and variable expressivity is the mode of 46 inheritance in this syndrome. Here, we are report a rare left lung hypoplasia case associated 47 with cardiac anomalies, with MRKH. 48 49 Case Report 50 A 31-year-old unmarried female patient presented with four years of cough with whitish 51 expectoration, left side dull aching chest pain, and difficulty in breathing. Breathlessness 52 progressed from Modified Medical Research Council grade 1 to 3 over these four years and 53 was not associated with palpitations, wheeze, or orthopnea. She had no history of loss of 54 weight, loss of appetite, abdominal distension, bilateral leg swelling, or reduced urine output. 55 History of pulmonary tuberculosis at the age of 2 years with an intake of antituberculosis 56 drug therapy was there but no documentation available regarding treatment. 57 58 She also had a history of amenorrhea but with no family history suggestive of Mullerian 59 tract/cardiac/renal/ lung/ skeletal anomalies. Initially patient underwent traditional medicine 60 treatment for amenorrhea after that patient went to another hospital to evaluate amenorrhea in 61 2017.Then she was referred to our institute for further evaluation. 62 63 During the evaluation, blind vaginal pouch with an absent uterus with a normal ovary found 64 in the ultrasound abdomen and pelvis. In view of suspecting MRKH syndrome following 65 investigations was done. Karyotyping 46XX, FSH (Follicle stimulating Hormone) =5.7 IU/L 66 (Normal Range-1.5-12.4 IU/L), LH (Luteinizing Hormone) =7.25 IU/L (1.09-9.2 IU/L), 67 Prolactin= 18ng/mL (Normal Range<25ng/mL), Testosterone= 0.7 nmol/L (Normal Range 68 0.5-2.4 nmol/L) and Estrogen 118 pg/ml(Normal Range 30-400pg/ml) and advised about 69 vaginoplasty and surrogacy. But patient did not come for a follow-up after that,in 2021 70 patient presented to the Obstetrics department with abdominal pain with outside Magnetic 71 Resonance Imaging (MRI) film, which showed right sided ovarian tumor with torsion and 72 features of MRKH syndrome such as absence of the uterus, hypoplastic vaginal canal with 73 normal bilateral kidney. 74 75 The patient underwent emergency laparotomy for ovarian torsion and the right ovary was 76 removed with a tumor followed by peritoneal cytology, and infracolic-omentectomy. Ovarian 77 tumour histopathology was a benign spindle cell tumor suggestive of leiomyoma with 78 torsion-related changes. 79 80 She had no pallor, clubbing, or clinically palpable generalized lymphadenopathy on 81 examination. Her room air saturation was 96%, her blood pressure was 110/70 mm of Hg, 82 and her Pulse rate was about 95/min. She had tanner grade 4 pubic hairs and breasts. 83 Examination of external genitalia showed a blind vagina. On chest examination, she had left 84 side tracheal deviation with the same side decreased vesicular breath sounds with biphasic 85 coarse inspiratory crepitations. Chest X-ray revealed cystic changes on the left side with 86 ipsilateral mediastinal and tracheal shift with compensatory hyperinflation on the right side 87 (Figure 1 a). Severe restrictive abnormality (FEV1/FVC-0.85, FVC-43%, FEV1-50% of the 88 predicted value) was found in spirometry. Given all these clinical and imaging features, a left 89 lung developmental anomaly was suspected and a contrast-enhanced Pulmonary Angiogram 90 (CTPA) done for the left main pulmonary artery size. CTPA showed left lung volume loss 91 with multiple thin and thick-walled cystic areas connected to lobar bronchus with no 92 evidence of lung parenchyma. Herniation of right upper lobe parenchyma into left hemi 93 thorax and small caliber of left main pulmonary artery [0.67cm], lobar and segmental arteries 94 than right side suggestive of left lung hypoplasia with cystic bronchiectasis with left superior 95 vena cava (Figure 1 b) and right aortic arch (Figure 1c) was noted. Fiber optic bronchoscopy 96 showed Right side and left lower lobe were normal bronchopulmonary segment with left side 97 upper lobe bronchus does not sudivide further (Figure 2 a&b). This confirmed our suspicion 98 of left lung developmental anomaly, and a diagnosis of left lung hypoplasia (Grade 3 monaldi 99 classification of hypoplasia) was made. 2D Echocardiography was done, which showed 100 moderate tricuspid regurgitation with dilated coronary sinus and left-sided superior vena 101 cava. Patient was advised for pulmonary rehabilitation (Breathing exercises, Active cycle 102 breathing technique and postural drainage for left lung), pneumococcal and influenza 103 vaccination and advised for pneumonectomy. However, the patient was not willing to 104 undergo for surgical procedure. The Patient was explained about vaginoplasty and surrogacy 105 in view of MRKH but patient was not willing to undergo surgical procedures. 106 107 Informed consent was obtained for publication of the patient’s clinical images and history. 108 109 Discussion 110 Two types of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome are there which include 111 type I (isolated) or Rokitansky sequence and type II or MURCS association (Mullerian duct 112 aplasia, renal dysplasia, and Cervical Somite anomalies.4The association of MRKH with lung 113 malformation mimicking bronchiectasis and heart malformations is very uncommon. Severe 114 cardiac defects evocating Holt-Oram or velocardiofacial-like syndromes requiring surgery 115 were reported in other case studies. The reported malformations were conotruncal defects 116 such as pulmonary valvular stenosis,5 aortopulmonary window.6But in our case presented 117 with left superior vena cava. 118 119 In most studies, uterine leiomyoma was found in patients with MRKH syndrome but very 120 rarely was ovarian leiomyoma. Ovarian tumour is difficult to examine in MRKH, mainly in 121 patients without vaginal reconstruction. Hence appropriate imaging is also needed to look for 122 pelvic mass during MRKH evaluation.7Pulmonary Hypoplasia is defined as reduced lung 123 tissue with hypo-plastic bronchi and vessels of varying degrees. Lung development starts 124 from the 26th day of intrauterine life and is completed in the early post-natal period.8 125 Pulmonary Hypoplasia may be primary or secondary. Primary pulmonary Hypoplasia is an 126 intrinsic defect in lung development with an incidence of 1-2 cases per 12,2000 live births. 127 Several mechanisms, like decreased hemi thoracic volume, decreased pulmonary vascular 128 perfusion, fetal movements, and lung fields are implicated in secondary pulmonary 129 hypoplasia. They are frequently associated with other congenital anomalies involving 130 urogenital, cardiovascular system, central nervous system, and musculoskeletal abnormalities 131 of the thoracic cage.9 Lung developmental disorders constitute three main categories 132 according to Boyden, which include agenesis (complete absence of the lung tissue), aplasia 133 (absent lung tissue with rudimentary bronchus ), and Hypoplasia (reduced lung tissues).10 134 Pulmonary Hypoplasia has a spectrum of clinical manifestations from asymptomatic to 135 respiratory failure.11 Most patients will develop respiratory distress as a newborn. However, 136 our patient presented with respiratory symptoms at the age of 2 years but was diagnosed with 137 pulmonary tuberculosis and treated; since then, the patient has had recurrent respiratory 138 infections, which led us to think of bronchiectasis as the primary lung pathology. 139 140 Diagnosis of pulmonary Hypoplasia with MRKH syndrome is rare in adulthood. Left lung 141 hypoplasia is more common than right, and in our patient, a chest x-ray was suggestive of 142 decreased volume loss with increased opacity on the affected side. A severe Restrictive 143 pattern was seen in spirometry, and computed tomography pulmonary angiography (CTPA) 144 was used to diagnose pulmonary Hypoplasia. Before diagnosing pulmonary Hypoplasia, we 145 must evaluate for other conditions similar to Hypoplasia, including non-cystic bronchiectasis, 146 and congenital airway malformations, and sequestration.12 In all these scenarios, the usually 147 standard caliber/size of same side pulmonary artery size will be expected. 148 149 Treatment for lung hypoplasia in adults were mainly supportive measures which include 150 recurrent infection control measures, expectorants for symptomatic management, and 151 management of other complications. Prophylaxis treatment for pneumococcus, Respiratory 152 syncytial virus (RSV), and influenza is recommended. Prognosis in such cases is based on the 153 remaining lung parenchyma and the presence of associated anomalies. 13 154 155 Cases with polycystic ovaries and ovarian tumors have been described in women presenting 156 otherwise with the usual 46, XX karyotype. In Yalavarthi S et al. study, the case of 157 sertoliform endometrioid carcinoma associated with MRKH syndrome is reported.14 158 In MRKH syndrome 40% of upper urinary tract malformations are found which includes 159 ectopia of one or both kidneys (17%), unilateral renal agenesis (23–28%), horseshoe kidney, 160 renal Hypoplasia (4%), and hydronephrosis. In MURCS patients 10–25% of them had 161 Auditory defects or deafness and 30–40% of the skeletal abnormalities of the spine were also 162 found in these cases.15 163 164 Case reports by Bach et al16 described the association of MRKH syndrome with pulmonary 165 agenesis. However, our case report is left lung hypoplasia with cardiac anomalies and MRKH 166 syndrome with ovarian Leiomyoma. 167 168 169 170 Conclusion 171 Pulmonary Hypoplasia affects the lung and airways and can be easily missed, especially in 172 those with previous pulmonary tuberculosis treatment history, unless the treating physician 173 has a high index of suspicion. We must evaluate anyone with recurrent respiratory symptoms 174 since childhood and primary amenorrhea for the congenital lung anomaly and other system 175 congenital malformations. Urinary anomalies are the most common anomaly associated with 176 MRKH syndrome, but lung hypoplasia association is infrequent. Once suspected, it would be 177 easy to diagnose with available investigations and further follow-ups in those with lung 178 hypoplasia with MRKH syndrome. 179 180 Authors’ Contribution 181 PU made the diagnosis in pulmonary medicine part and helped in writing the case report. AA 182 diagnosed MRKH and helped in revising case report. SC wrote the paper and followed the 183 case and collected details. DP helped in drafting article and images. VK helped in writing 184 report. All authors approved the final version of the manuscript. 185 186 References 187 1. Laudy JA, Wladimiroff JW. The fetal lung. 2: Pulmonary hypoplasia. Ultrasound Obstet 188 Gynecol. 2000;16:482–94. DOI: 10.1046/j.1469-0705.2000.00252.x 189 2. Kant S. UNILATERAL PULMONARY HYPOPLASIA – A CASE REPORT. Lung 190 India . 2007;24:69–71. DOI: 10.4103/0970-2113.44215 191 3. Griffin JE, Edwards C, Madden JD, Harrod MJ, Wilson JD. Congenital absence of the 192 vagina. The Mayer-Rokitansky-Kuster-Hauser syndrome. Annals of Internal Medicine. 193 1976;85:224–36. DOI: 10.7326/0003-4819-85-2-224 194 4. Opitz JM. Vaginal atresia (von Mayer-Rokitansky-Küster or MRK anomaly) in 195 hereditary renal adysplasia (HRA). American Journal of Medical Genetics. 196 1987;26:873–6. DOI: 10.1002/ajmg.1320260414 197 5. Kula S, Saygili A, Tunaoğlu FS, Olguntürk R. Mayer-Rokitansky-Küster-Hauser 198 syndrome associated with pulmonary stenosis. Acta Paediatr. 2004;93:570–2. 199 DOI: 10.1080/08035250310023773 200 6. Ulrich U, Schrickel J, Dorn C, Richter O, Lewalter T, Lüderitz B, et al. Mayer-von 201 Rokitansky-Küster-Hauser syndrome in association with a hitherto undescribed variant 202 https://doi.org/10.1046/j.1469-0705.2000.00252.x https://doi.org/10.7326/0003-4819-85-2-224 https://doi.org/10.1002/ajmg.1320260414 https://doi.org/10.1080/08035250310023773 of the Holt-Oram syndrome with an aorto-pulmonary window. Human Reproduction. 203 2004;19:1201–3. DOI: 10.1093/humrep/deh198 204 7. Miao Y, Wen J, Huang L, Wu J, Zhao Z. Diagnosis and Management of Ovarian Tumor 205 in Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome. Biomed Research 206 International . 2018 ;2018:2369430. https://doi.org/10.1155/2018/2369430 207 8. Papadopoulos D, Misthos P, Chorti M, Skopas V, Nakou A, Karagianidis N, et al. 208 Unilateral pulmonary hypoplasia in an adult patient. Monaldi Archives for Chest 209 Disease. 2018;88. DOI: 10.4081/monaldi.2018.829 210 9. Liners J, Médart DL, Collignon L. Primary Pulmonary Hypoplasia. Journal of the 211 Belgian Society of Radiology . 2019 ;103. DOI: http://doi.org/10.5334/jbsr.1717 212 10. Boyden EA. Developmental anomalies of the lungs. The American Journal of Surgery. 213 1955;89:79–89. DOI: 10.1016/0002-9610(55)90510-9 214 11. Gülen F, Kar S, Midyat L, Demir E, Özyurt S, Özyürek AR, et al. A rare clinical 215 presentation of pulmonary hypoplasia. Open Journal of Pediatrics. 2011;01:75–8. 216 DOI:10.4236/ojped.2011.14018 217 12. 3D Imaging in Unilateral Primary Pulmonary Hypoplasia in an Adult: A Case Report. 218 https://www.hindawi.com/journals/crira/2011/659586/ 219 13. Thomas RJ, Lathif HC, Sen S, Zachariah N, Chacko J. Varied presentations of unilateral 220 lung hypoplasia and agenesis: a report of four cases. Pediatric Surgery International. 221 1998;14:94–5. DOI: 10.1007/s003830050447 222 14. Yalavarthi S, Jadhav VA, Kumar SS, Pavani M. Mayer–Rokitansky–Kuster–Hauser 223 syndrome: Syndrome of Mullerian agenesis – A report of two cases. Medical Journal of 224 Dr DY Patil University . 2017;10:207. DOI: 10.4103/0975-2870.202095 225 15. Morcel K, Watrin T, Pasquier L, Rochard L, Le Caignec C, Dubourg C, et al. Utero-226 vaginal aplasia (Mayer-Rokitansky-Küster-Hauser syndrome) associated with deletions 227 in known DiGeorge or DiGeorge-like loci. Orphanet Journal of Rare Disease. 2011 ;6:9. 228 16. Bachh AA, Pulluri S, Beigh A, Raju C, Deshpande R. Pulmonary Aplasia with Unusual 229 Associations in a Woman. Iranian Journalof Medical Sciences. 2014;39:148–51. 230 PMID: 24644386 231 232 https://doi.org/10.1093/humrep/deh198 https://doi.org/10.1155/2018/2369430 https://doi.org/10.4081/monaldi.2018.829 http://doi.org/10.5334/jbsr.1717 https://doi.org/10.1016/0002-9610(55)90510-9 http://dx.doi.org/10.4236/ojped.2011.14018 https://doi.org/10.1007/s003830050447 https://pubmed.ncbi.nlm.nih.gov/24644386 233 Figure 1: A: Chest x-ray demonstrating a mediastinal shift to the left with crowding of ribs 234 on the left with hypolucent opacity with ectatic changes on the left side. B: CTPA showing a) 235 left lung volume loss with multiple thin and thick-walled intercommunicating cystic areas 236 and b) decreased caliber of the left main pulmonary artery (0.67mm) and left superior vena 237 cava (asterisk), (C) CTPA showing right aortic arch(asterisk) 238 239 Figure 2: A: Fibreoptic bronchoscopy shows the main carina with bilateral patent bronchi. B: 240 Left side secondary carina with lobar bronchi (White arrow showed left upper lobe single 241 bronchial opening without subdivision) 242