Precocious puberty or growth hormone deficiency as initial presentation in Mayer-Rokitansky-kuster-Hauser syndrome: a clinical report of 5 cases

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS; OMIM # 277,000) is a congenital syndrome characterized by complete absence or hypoplasia of Mullerian structures, including fallopian tubes, uterus and upper two-thirds of the vagina. Notably, external genitalia are normal. MRKHS is classified into two subtypes: MRKHS type 1 is associated with isolated abnormalities of the reproductive system, whereas MRKHS type 2 also has an array of other anomalies, including renal and skeletal malformations, short stature, ontological anomalies and other defects [1]. MRKHS was first described by Mayer in 1829 with an estimate female incidence of 1 in 5,000 live births [2]. The molecular basis of MRKHS remains elusive, although a few candidate genes are considered likely.

Generally, patients affected with MRKHS have a normal (46, XX) karyotype, as well as normal ovarian function and age-appropriate secondary sex characteristics (breast growth, body hair, body proportions) [3]. Typically, MRKHS girls are clinically healthy and are not identified until late puberty due to absent of menarche or dyspareunia [1]. To date, endocrine function in MRKHS has been inadequately investigated, but allegedly endocrine function is intact [4]. Herein, the presenting endocrine disorders of five Chinese children with MRKHS are delineated.

Detailed data from five MRKHS patients from July 2017 to December 2020 in the Fuzhou Children’s Hospital of Fujian Medical University was collated. This study was reviewed and approved by the Ethics Committee of Fuzhou Children’s Hospital of Fujian and was conducted in agreement with the Declaration of Helsinki Principles. Each of the patients and parents gave informed consent.

MRKHS is an uncommon developmental disorder and is often diagnosed due to primary amenorrhea in late puberty, whereas some patients are coincidentally identified in early infancy due to associated anomalies or unrelated ailments [5]. Once the diagnosis of MRKHS is suspected, confirmation is based on further investigation including imaging (Ultrasound/MRI), karyotyping/chromosome analysis and serum hormone status. MRI is considered to be the preferred procedure, and is a more suitable option in pediatric patients [6]. All five of our patients fulfilled the clinical diagnostic criteria for MRKHS. It is noteworthy that both advanced puberty and GHD occurred in one patient, which is quite distinct from the typical presentation of MRKHS. The clinical characteristics and management of these patients are summarized in the Table 1. We painstakingly reviewed the literature and found that this tandem hormone abnormality (PP, GHD) is atypical. Only two patients with PP in MRKHS have been previously reported [7, 8], and patient with GHD has never been reported.

There are two major types of MRKH syndrome. Type I is characterised by congenital aplasia of the uterus and upper two-thirds of the vagina. Type II also incorporates extragenital/extra-Müllerian malformations, including vertebral, cardiac, urological (upper tract) and ontological anomalies [9]. The MRKHS phenotype is highly variable. Poorly developed, or agenesis of vagina or uterus can be found. The ovaries usually arise from a separate embryologic source (urogenital ridge), and are generally normal, although abnormal ovarian function and location have been reported [10, 11]. A significant proportion of MRKHS patients have associated extragenital malformations. Of these, renal malformations are the most prevalent associated anomalies (~ 33%) [2], incorporating a wide spectrum that includes renal agenesis, horseshoe kidney, pelvic kidney and renal cysts. In our study, bilateral polycystic kidneys were found in one patient. A prevailing theory for renal malformations posits the close physical and temporal proximity development process between Mullerian and Wolffian ducts [12]. A host of other MRKHS malformations are as follows: skeletal anomalies (e.g., vertebral arch disturbances, scoliosis, hypoplasia of the wrist, bilateral tibial longitudinal deficiency, hypoplastic sternum), hearing impairment, cardiac malformations, and umbilical/diaphragmatic/abdominal wall hernia. Co-existing anomalies account for the clinical heterogeneity and complexity of MRKHS. The VCUAM (vagina, cervix, uterus, adnexae-associated malformation) system is the consensus classification to categorize the associated malformations in MRKHS [13]. In our series, only one patient could be classified as type 2.

The congenital nature and multiple reports of familial aggregates implicate a genetic etiology [14]. A deletion at chromosome 17q12, spanning more than 100 kb of genomic DNA and containing HNF1B, was detected in one patient. The 17q12 region genes is a relatively common CNV in both MRKHS types 1 and 2 [15]. Deletions of 17q12 range from 1.2–1.8 Mb in size, and no association between disparate deletion sizes and phenotypic have been discerned [16]. HNF1B resides within this region and could plausibly be a promising genetic candidate for MRKHS [17]. This gene is highly expressed in Wolffian and Müllerian ducts and plays a vital role in the development and differentiation of liver, kidney, pancreas and genital tract [15]. HNF1B haploinsufficiency contributes to impairment of uterine development by down-regulating key genetic factors involved in urogenital development, such as LHX1, PAX2, and WNT9B [18]. Heterozygous mutations or whole gene deletions of HNF1B gene are associated with variable renal abnormalities, such as renal cysts, and hypo-dysplasia [19]. However, these genetic abnormalities are not described in isolated uterine defects [20]. No mutations in HNF1B have been detected with MRKHS [21]. Although 17q12 CNV has been reported in MRKHS, other mutated genes within this region may be causative.

Due to the complex clinical characteristics and etiology of MRKHS, childhood presentation can vary. Four patients in our study presented with premature thelarche and advanced BA, and premature pubarche in one of them. Notably, early onset of puberty is the cardinal feature in our report, distinct from the typically initial adult manifestation of MRKHS. A GnRH test was performed which confirmed CPP in one patient (case 3) and incomplete precocious puberty confirmed in three patients. PP accounts for the bone maturation and reduced final adult height. To our knowledge, only two MRKHS with PP have been previously reported. The first patient was reported in 2001 by Raybaud et al. [7], who described a 8 year-8 month- old girl with obesity, CPP and type 1 MRKHS. The other patient was a 7-year-old girl with urinary incontinence, CPP and type 2 MRKHS ((vaginal agenesis, absence of uterus and single pelvic kidney) [13]. The most common etiology of PP is the premature activation of the hypothalamic-pituitary–gonadal (HPG) axis. Pineal cyst and Rathke cyst were detected by MRI in three of our patients. Recently, the prevalence of pineal cyst (0.8%) and Rathke cyst (2%) have been reported in 251 girls with CPP [22]. One conceivable explanation is that a cyst somewhat abrogates the normal prepubertal gonadotropin inhibition [23, 24]. The pathogenetic mechanism for PP in MRKHS, however, remains elusive. A normal steroid hormone interaction between the ovaries and uterus is essential for normal regulatory mechanisms, especially during the menstrual cycle [25]. Strissel et al. [26] proposed that the normal ovarian-uterine steroid communication is disrupted in MRKHS. Accordingly, we conjecture that the missing crosstalk between ovary and uterus may disturb the hypothalamic feedback system, thereby promoting premature gonadotropins secretion. Indeed, a significantly higher levels of LH and FSH are observed in MRKHS compared to controls [27], and an increased incidence of aberrant hormone levels in patients with MRKHS, including hyperprolactinemia and hyperandrogenemia, further support our hypothesis [27, 28]. Taken together, based on the patients reported in this study along with those previously published, we opine that early puberty development in MRKHS is not uncommon.

Short stature, a common malformation in the type II MRKHS, was found in one of our five patients. GH stimulation tests revealed GHD. Although short stature is known to be associated with type II MRKHS, the underlying etiology is not fully understood. Both skeletal anomalies and partial duplication of pseudoautosomal Xpter region 1, containing the SHOX gene for short height, could be responsible [2, 29]. Our patient presented with both GHD and early puberty. The pathogenesis of GHD is unclear. Studies of additional MRKHS patients may determine the factors that disturb ancillary hypothalamic-pituitary pathways beyond the HPG axes. Moreover, it is noteworthy that a postnatal growth reduction has been reported in patients with HNF1B deletion and HNF1B-knockout mice, however, whether this is due to growth hormone deficiency is uncertain [30, 31].

Information related to gonadotrophin releasing hormone agonist (GnRHa) or GH therapy in patients with MRKHS are lacking. Until now, only one patient with PP has been reported in a child with MRKHS who was treated with GnRHa [7]. As for GH therapy, twelve months of GH treatment in a short MRKHS patient induced a significant increase in height without complications [32]. In this study, we did not prescribe GnRHa to the patient with PP because she had a normal predict height notwithstanding her advanced BA. Our patient is currently receiving rhGH therapy and given the positive growing response without adverse effects, we are optimistic about her final height.

In summary, four girls with MRKHS had precocious puberty, and one had GHD. The distinctive finding is the commonality of abnormal puberty onset and growth progression in MRKHS. Although it remains unclear whether the deletion of 17q22 is involved in GHD, we opine that the endocrinological disorders in our five patients may not be a stochastic phenomenon and may be more common than realized. Further study in a larger number of MRKHS children would clarify the pathophysiology of abnormal puberty onset and growth progression.