Co-Occurrence of Sotos Syndrome and Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome in 2 Patients

Authors: Manahil Mustafa, Mary K Mitscher, Nancy B Johnson, John S Fuqua

Abstract

Sotos syndrome is an autosomal dominant condition caused by a pathogenic variant of NSD1 and characterized by a distinctive facial appearance, learning disability, and overgrowth. Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a congenital disorder characterized by agenesis or aplasia of the uterus and upper part of the vagina in females with a normal female karyotype. The coexistence of the 2 syndromes has been reported only twice to date. We describe 2 girls with Sotos syndrome who presented with primary amenorrhea. The patient in case 1 had central precocious puberty diagnosed at age 6.5 years, which was appropriately managed for 2 years. The patient in case 2 had congenital hypothyroidism due to thyroid aplasia, treated with levothyroxine. Investigations in both girls revealed normal gonadotropin and estradiol levels. Pelvic ultrasound and magnetic resonance imaging showed absence of the uterus and the presence of normal ovaries. Based on these findings, both patients were diagnosed with müllerian agenesis/MRKH. The presence of Sotos and MRKH syndromes in these 2 patients, along with the 2 previously documented cases, might be coincidental. However, with 4 reported cases, the possibility exists for a rare link between Sotos syndrome and MRKH. Additionally, the psychosocial effect of infertility should not be underestimated.

Introduction

Sotos syndrome is a genetic condition characterized by a constellation of characteristic facial appearance, overgrowth, and learning difficulties. The diagnosis is confirmed by identification of a heterozygous pathogenic variant in NSD1 (nuclear receptor-binding SET domain protein 1), which encodes a histone methyltransferase implicated in chromatin regulation.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, also known as müllerian aplasia/agenesis, is characterized by aplasia of the uterus and upper part of the vagina in 46, XX females [1]. Patients usually present with primary amenorrhea and normal development of secondary sexual characteristics. The estimated prevalence of MRKH syndrome is about 1 in 5000 live female births [2]. The etiology of MRKH syndrome remains unclear. For many decades, MRKH syndrome was believed to be sporadic and not caused by genetic mutations. However, recent advancements in molecular testing have opened the possibility of a genetic etiology for the condition [3]. Here, we present 2 girls with Sotos syndrome who were found to have concomitant MRKH syndrome. The co-occurrence of Sotos syndrome with MRKH is important, as it represents a rare association not widely documented in the existing literature, with only 2 similar cases previously reported. Understanding this connection could provide valuable insights into the broader implications of Sotos syndrome and its potential effect on reproductive development.

Case Presentation

Case 1

A 15-year-old girl with Sotos syndrome, confirmed by a pathogenic variation in NSD1 at age 3 years, presented to the endocrine clinic with primary amenorrhea. She was born at 37 weeks’ gestation with a birth weight of 2160 g and a length of 49.5 cm. She underwent repair of an inguinal hernia at age 3 months, which recurred and was repaired again at age 18 months. Developmental delay was noted. At age 6.5 years, she exhibited breast development and facial acne but lacked pubic or axillary hair and vaginal bleeding. Bone age (BA) at 6 years and 11 months was equivalent to that of a 10-year-old, and brain magnetic resonance imaging (MRI) revealed ventricular enlargement, but the pituitary gland was normal. She was diagnosed with central precocious puberty (CPP), which was treated with a histrelin implant. The implant was removed at age 11 years, and at a subsequent follow-up 4 months later she had Tanner stage 3 breast development, indicating cessation of pubertal suppression. At age 15 years, she returned to the clinic with primary amenorrhea despite ongoing breast development and without vaginal discharge, spotting, or bleeding. She denied hirsutism, cyclic abdominal pain, galactorrhea, or recent substantial weight changes. Her intensive physical activity, including 2 hours of swimming daily and weight training, led to an initial consideration of hypothalamic amenorrhea. On physical examination, her weight was 66.4 kg, and her height was 171 cm. Her blood pressure was 119/73 mm Hg, her heart rate was 90 bpm, and her body mass index was 22.7. Physical findings included a large head, broad forehead, narrow jaw, Tanner stage 5 breast and pubic hair development, and normal axillary hair. The remainder of her physical examination was normal.

Case 2

A 14-year-old girl with Sotos syndrome presented for evaluation of primary amenorrhea. She was delivered at term via cesarean delivery, with a birth weight of 3466 g and a length of 53 cm. At birth, she exhibited dysmorphic features consistent with Sotos syndrome, which was later confirmed genetically. Shortly after birth, she was diagnosed with congenital hypothyroidism through newborn screening, and imaging revealed thyroid aplasia. She spent 25 days in the neonatal intensive care unit for feeding difficulties. Her medical history included a bicuspid aortic valve and a dilated ascending aorta. Additionally, she had received treatment for attention deficit disorder and behavioral problems and had participated in Applied Behavior Analysis therapy. At age 14 years, she developed a large pericardial effusion of unknown etiology with cardiac tamponade. She had severe obstructive sleep apnea with hypoventilation, managed with continuous positive airway pressure therapy. She had been receiving levothyroxine since infancy and reported no symptoms of hypothyroidism or hyperthyroidism. She had normal secondary sexual characteristics but had not had menarche. There was no hirsutism, cyclic abdominal pain, galactorrhea, or recent substantial weight changes.

On physical examination, the patient weighed 82.2 kg and measured 162 cm, with a body mass index of 31.3. Notable findings included macrocephaly, frontal bossing, down-slanting palpebral fissures, and abnormal dentition. Breast development was at Tanner stage 4 with well-stimulated tissue. Pubic hair was Tanner stage 5. The remainder of her physical examination was normal.

Diagnostic Assessment

Case 1

Laboratory results were as prolactin 17 ng/mL (17 µg/L) (reference range, 3.34-26.72 ng/mL; 3.34-26.72 µg/L), thyrotropin (TSH) 1.558 µIU/mL (1.588 mU/L) (reference range, 0.530-3.590 µIU/mL; 0.530-3.590 mU/L), free thyroxine 0.85 ng/dL (10.94 pmol/L) (reference range, 0.60-1.40 ng/dL; 7.72–18.02 pmol/L), β-human chorionic gonadotropin negative, luteinizing hormone (LH) 4.54 mIU/mL (4.45 IU/L) (reference range for adult women, 1.0-11 mIU/mL; 1.0-11 IU/L), follicle-stimulating hormone (FSH) 4.49 mIU/mL (4.49 IU/L) (reference range for adult women, 2.5–9.1 mIU/mL; 2.5–9.1 IU/L), estradiol 66.1 pg/mL (242.6 pmol/L) (reference range, 2.0-259.0 pg/mL; 7.34-950 pmol/L), and free testosterone 4.4 pg/mL (15.2 pmol/L) (reference range, 1.2-7.5 pg/mL; 4.1-26.0 pmol/L).

Administration of medroxyprogesterone, 10 mg for 10 days, did not result in withdrawal bleeding. Pelvic ultrasonography demonstrated normal ovaries, but no uterus was visualized. A pelvic MRI revealed a blind-ending vaginal canal with an absent uterus and cervix (Fig. 1), confirming MRKH syndrome.

Case 2

Thyroid function tests were consistently normal. A pelvic ultrasound obtained at age 14 revealed normal pubertal ovaries and normal fallopian tubes. No uterus was seen. Despite normal secondary sexual characteristics, the patient remained premenarchal until age 15, prompting further imaging. Computed tomography of the pelvis to evaluate abdominal pain and vomiting confirmed the presence of normal ovaries but noted that the “uterus appears small and prepubertal in size.” Laboratory results at that time included estradiol of 24 pg/mL (88.1 pmol/L) (reference range, 2.0-259.0 pg/mL; 7.34-950 pmol/L), FSH of 4.4 mIU/mL (4.4 IU/L) (reference range for adult women, 2.5-9.1 mIU/mL; 2.5-9.1 IU/L), LH of 2.0 mIU/mL (2.0 IU/L) (reference range for adult women, 1.0-11 mIU/mL; 1.0-11 IU/L), and TSH of 1.66 mIU/L (1.166 µIU/mL) (reference range, 0.530-3.590 mIU/L; 0.530-3.590 µIU/mL). A repeat laboratory evaluation at age 17 showed estradiol of 82 pg/mL (264.3 pmol/L), FSH of 4.5 mIU/mL (4.5 IU/L), and LH of 9.7 mIU/mL (9.7 IU/L). A dedicated pelvic MRI at that time again showed normal adult size ovaries, but no uterus was seen (Fig. 2).

Treatment

Case 1

No specific treatment was initiated for the MRKH syndrome at the time, but the patient was advised on potential future management options for reproductive health and support.

Case 2

The patient continued with thyroid replacement therapy and continuous positive airway pressure for obstructive sleep apnea. There were no specific treatments initiated for the MRKH syndrome at the time of evaluation.

Outcome and Follow-up

Both patients’ conditions remained stable with continued management for their various health issues.

Discussion

Sotos syndrome is a genetic disorder characterized by a unique combination of facial features, excessive growth, and cognitive challenges. The diagnosis is typically confirmed through molecular genetic testing, which identifies a heterozygous pathogenic variant in the NSD1 gene, present in 90% of patients [4]. In addition to the hallmark triad, patients may present with various other clinical features, including autism spectrum disorder, advanced BA, cardiac anomalies, brain abnormalities, joint hyperlaxity (with or without pes planus), scoliosis, and seizures [5].

Endocrine manifestations reported in individuals with Sotos syndrome beyond the well-documented overgrowth and advanced BA include hyperinsulinemic hypoglycemia, hypospadias, and cryptorchidism [6, 7]. A rare endocrine manifestation observed in one of our patients is CPP, which occurred at age 6.5 years. She presented with breast development and facial acne and her brain MRI was unremarkable apart from ventriculomegaly, a common finding in patients with Sotos syndrome. The association between Sotos syndrome and CPP has been reported in only 4 other patients in the literature [8-11]. Additionally, our second patient exhibited congenital hypothyroidism due to thyroid aplasia, a finding reported in just 2 other people with Sotos syndrome. The first case was documented by Tatton-Brown et al [4], who studied the phenotype of 266 individuals with a confirmed NSD1 pathogenic variant, noting one case of thyroid hypoplasia. The condition was also reported by Verma et al [12].

MRKH syndrome is a condition affecting 46, XX females and characterized by the absence of the uterus and the upper portion of the vagina. Patients with MRKH syndrome often present with primary amenorrhea while displaying normal secondary sexual characteristics. The clinical manifestations of MRKH syndrome can vary considerably among patients, leading to a diverse range of presentations [13]. This syndrome is categorized into 2 type I, which involves isolated uterovaginal aplasia, and type II, which encompasses additional extragenital anomalies. These extragenital anomalies are frequently associated with malformations of the kidneys, skeletal system, ears, or heart.

The combination of Sotos and MRKH syndromes is rare and has been reported in only 2 cases in the literature [14, 15]. In all 4 reported cases, the girls experienced spontaneous puberty and developed normal secondary sexual characteristics (Table 1). All patients had normal hormonal evaluations, effectively excluding primary and central hypogonadism as underlying causes of amenorrhea. The only exception noted is the patient described by Cattoni et al [14], who presented with breast hypoplasia of unknown etiology, despite a robust estradiol level.

The connection between Sotos syndrome and MRKH syndrome highlights the importance of careful evaluation in patients diagnosed with Sotos syndrome, particularly regarding reproductive tract abnormalities. Imaging studies performed for conditions associated with Sotos syndrome, such as scoliosis or renal anomalies, may permit the incidental discovery of MRKH syndrome. As the presence of MRKH syndrome substantially affects reproductive health and has implications for psychosocial well-being, early detection through imaging studies in the setting of delayed onset of menses is advisable. Identifying any potential anomalies in the uterus or upper vagina can allow for the timely addressing of concerns related to reproductive function and the implications of associated genetic conditions. In affected patients, the diagnosis of MRKH makes conception impossible, leading to fertility issues. This condition often affects patients’ emotional well-being and personal relationships. Thus, integrating awareness of MRKH syndrome into the clinical management of patients with Sotos syndrome will allow for comprehensive care and support of affected individuals and their families.

MRKH syndrome is typically considered sporadic, with no specific genetic pathogenic variant identified to date. However, the presence of multiple familial cases and recent research indicating a heterogeneous etiology suggest a potential genetic component [16, 17]. The reported association between MRKH and Sotos syndrome, although rare, raises the possibility of a shared genetic or developmental pathway that warrants further exploration. Given the lack of a known genetic cause for MRKH and the emerging evidence of familial clustering, future research, particularly with whole-genome sequencing, could provide valuable insights into the genetic underpinnings of both conditions and inform the evaluation and management of individuals with Sotos syndrome who present with primary amenorrhea.

Learning Points

• The co-occurrence of Sotos and MRKH syndromes in these individuals could indicate a common pathophysiologic underpinning, although it could instead be a random occurrence.
• Delayed menarche in girls with Sotos syndrome despite normal secondary sexual characteristics and unremarkable endocrine testing requires thorough investigation, including imaging studies, to rule out müllerian agenesis.
• Confirmation of müllerian agenesis through imaging illustrates the importance of addressing reproductive health concerns in patients with Sotos syndrome, providing appropriate counseling, and supporting future management.