Abstract
Objective
To highlight the challenges in diagnosing 46, XY disorder of sex development related to MYRF mutation.
Methods
We present an unusual case of a 12-year-old female child came for enlargement of clitoris and initially diagnosed as partial androgen insensitivity syndrome (AIS).
Results
On examination, the patient’s vulva was found virilized with 3cm-long clitoris. Her peripheral blood karyotype was 46, XY. The ultrasound showed an empty pelvis and hormone results confirmed hyperandrogenism. Therefore, the partial AIS was suspected, but the following whole exon sequencing indicates a pathological missense mutation in MYRF. Further investigation and surgery did not reveal any brain, heart, lung or diaphragm lesions related to MYRF, but only maldeveloped internal genitalia and a persistent urachus. Her serum testosterone dropped to normal after surgical removal of the remaining ipsilateral testis and epididymitis without spermatogenesis as shown by pathology.
Conclusion
Due to the karyotype, hyperandrogenism, empty pelvis but a virilism after puberty, the patient was initially diagnosed as partial AIS. This misleading clinical diagnose will not be verified as the MYRF mutation if without the whole exon sequencing, particularly in the absence of obvious brain, heart, lung and diaphragm lesions as in this case.
Case report
The myelin regulatory factor gene (MYRF, MIM#608329) containing 26 exons, locates in chromosome 11q12.2 [Citation1]. MYRF, a transcription factor, regulates the myelination of central nervous system and celom formation, affecting the development of brain, heart, lungs, diaphragm, gonads and genitourinary tract [Citation2–4]. Mutations of MYRF follows an autosomal dominant mode, and results in either mild encephalopathy and reversible myelin vacuolization (MIM# 618113) or cardiac-urogenital syndrome (MIM# 618280). Here, we describe a case manifested primarily mimics the partial androgen insensitivity syndrome (AIS). Written informed consent was obtained from the couple (the patient’s parents) mentioned in this article for publication of medical history related to this case.
The female patient was 11-year-old without any obstetrical history. Her growth, development, academic performance and physical ability were comparable to her peers. In her 10 years old, her clitoris was found gradually growing to 3 cm in length. Simultaneously her breast development belonged to Tanner stage I and pubic hair Tanner stage II, and her height had reached to 152 cm. Apart from those, no adolescent signs appeared. On examination, no beard, prominentia laryngea or acne was found. The labium majus was darkened, the posterior part of labium minus was fused with elevated posterior perineal symphysis. The openings of urethral and vaginal were close but separated and a blind-ended vagina was detected. Mass spectrometry showed testosterone (T) 2.61 ng/mL, dehydroepiandrosterone sulfate (DHEAS) 746.53 ng/mL, estradiol (E2) 25 pg/mL, anti-mullerian hormone (AMH) 0.17 ng/mL, progesterone (P)<0.05 ng/mL, FSH 112.19 IU/L, LH 46.89 IU/L, 17α-OH-progesterone (17OHP) 0.57 ng/mL, aldosterone (ALDO) 0.082 ng/mL, cortisol (F) 53.70 ng/mL and adrenocorticotropic hormone (ACTH) 36 pg/mL (reference range: T < 0.41 ng/mL, 562 < DHEAS < 5117ng/mL, 17OHP < 2.30 ng/mL, ALDO < 0.22 ng/mL, 28 <F < 246 ng/mL, 7.2 < ACTH < 63.3 pg/mL). In addition, her peripheral blood lymphocyte karyotype was 46,XY. Pelvic ultrasound did not present any structure of uterus or adnexa, and no mass was found in inguinal canal either. Therefore, this patient was clinically diagnosed as partial AIS at first due to her karyotype, hyperandrogenism, empty pelvis but a virilism after puberty. However, the further whole exon sequencing (trio) did not confirm any mutation in androgen receptor gene, but a de novo and novel heterozygous pathogenic missense mutation (PVS1 + PS4 + PM2_Supporting + PS2) in MYRF exon 15 (c.2174 G > C, p.Ser725Thr, NM_001127329) [Citation5], which was not inherited from either parent. Then thorough laboratory works related to MYRF mutation were arranged, but nothing further abnormal detected. Laparoscopic exploration showed a remaining urachus, splitting the pelvis into two compartments. In its left, a 2 cm infantile uterus located on the bottom of pelvis but nothing in the right. A 1 cm long fallopian tube-like tissue could be seen left to the left vena iliaca externa, but separated from the uterus. No left gonad was detected from the left pelvis or inguinal canal, therefore, we only removed the tube-like tissue. In the right pelvis, an isolated 1.5*1.0 cm testis-like gonad was removed. Through the hysteroscope, we noticed a complete longitudinal vaginal septum. The left cavity was covered by the epithelial with plica and end up with a maldeveloped cervix about 5 mm in diameter; the right cavity was a blind end and the epithelial was smooth. Both cavities were about 7 cm in length. At last, a clitoroplasty with preservation of neurovascular pedicles was successfully conducted and her perineum presents as a female appearance. Two days after surgery, serum T level decreased from 2.61 to 0.38 ng/mL. Pathology reported the left side tissue was in accord to a fallopian tube histology, while the tissue from the right was a maldeveloped testis and an epididymitis without spermatogenesis.
Congenital cardiac structural abnormalities are the most common manifestation in MYRF-deficient patients and discovered in more than 90% cases [Citation4,Citation6]. Among them, the most frequent and lethal scenarios are hypoplastic left heart, followed by scimitar syndrome.
Urogenital structural defects are the second common anomalies. In affected 46,XY individuals, ambiguous (hypospadias, cryptorchidism, and micropenis) to completely feminized genitalia can be seen, as well as chordee and persistent urachus as in this girl [Citation6]. In both chromosomal sex types, the migration and development of sex cord-mesenchymal tissue can be interfered. Therefore, their gonads may be maldeveloped or degraded in either or both side and the gonadotropins are generally high due to gonadal failure. For this patient, her karyotype is 46,XY which is in line with her right side gonadal pathology–maldeveloped testis and epididymitis, and no Mullerian duct appears in the right side. However, the missing ipsilateral Wolffian duct and a female external genitalia indicated the deprivation of T production since fetal stage. After onset of adolescence, the remaining functional Leydig cells generate slightly higher T level, which trigger the enlargement of clitoris and labia. All of the above presentations mislead us to a diagnosis of partial AIS initially. Besides, we raised a novel manifestation of MYRF mutation, with isolated DSD but not cardiac, diaphragmatic or neural lesions.
Congenital diaphragmatic hernia ranks the third most prevalent structural defect. More than 60% cases are affected, and often accompanied by lung hypoplasia [Citation6], underlining the significance of MYRF in regulating lung development [Citation3]. Therefore, some scholars suggest to rename this MYRF deficiency as cardiac-urogenital-diaphragm-lung (CUDL) syndrome.
Up to now, less than 30 cases of MYRF mutation have been reported [Citation4,Citation7]. The haploinsufficiency of MYRF often leads to syndromic presentations, characterized as CUDL [Citation8]. To our knowledge, this is the first case with merely genital malformation and a novel pathological mutation was found in MYRF (c.2174 G > C).
Ethical approval
The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Peking Union Medical College Hospital. Written informed consent was obtained from the couple (the patient’s parents) mentioned in this article for publication of medical history and images related to this case.
Author contribution
ZDD collected raw data and wrote the main manuscript text; TQJ was responsible for the conceptualization, design and funding acquisition. All authors reviewed the manuscript and agreed for publication.
Acknowledgements
We are grateful to the patient’s family who agree for the report of this case.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
All data generated or used during the study appear in the submitted article. The dataset of gene mutation is in ClinVar (www.ncbi.nlm.nih.gov/clinvar) and the accession number is SUB13949291.
Additional information
Funding
References
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