Familial Case of Morris Syndrome: Clinical Observations

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INTRODUCTION

Sexual development during both prenatal and postnatal periods is largely determined by adequate levels of androgens. The period of embryogenesis is critical for the development of the reproductive system; therefore, pathological changes occurring at 8–14 weeks of gestation may lead to various disorders. In addition, such pathological changes are associated with mutations in the androgen receptor (AR) gene and abnormal secretion of sex hormones. The human AR gene is located on the X chromosome, at Xq11–12, and has 8 exons encoding a peptide of 919 amino acid residues [1, 2]. Androgen receptors are ligand-dependent transcription factors consisting of four functional domains: a large N-terminal domain (residues 1–555), a DNA-binding domain (residues 556–623), a hinge domain (residues 624–665), and a C-terminal ligand-binding domain (residues 666–919) [3]. Pathogenic variants in the AR gene result in reduced or lost AR function, leading to peripheral androgen resistance and defining the phenotypic characteristics of patients [4]. Three clinical variants are distinguished based on genotype: complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS), and mild androgen insensitivity syndrome (MAIS) [3, 5, 6].

Complete androgen insensitivity syndrome (also known as testicular feminization syndrome, Morris syndrome or OMIM 312300), is an X-linked genetic disorder associated with impaired sex differentiation [1, 7, 8]. Its prevalence ranges from 1 : 20,000 to 1 : 99,000 among individuals with a 46,XY karyotype [7, 9, 10]. According to retrospective studies, the incidence of CAIS among girls with inguinal hernias varies from 0.8% to 2.4%, whereas in patients with diagnosed testicular feminization syndrome, bilateral inguinal hernias are found in 50% to 80% of cases [3]. The condition was first described in 1953 by J. Morris in a cohort of 82 patients. He identified the distinguishing features of males with pseudohermaphroditism, including a female phenotype with well-developed secondary sexual characteristics, sparse axillary and pubic hair, underdeveloped labia, a blind-ending vagina, and the presence of testes located intra-abdominally or along the inguinal canal. These testes are capable of producing estrogens and androgens, and urinary gonadotropin levels are elevated [3, 11]. Patients with testicular feminization syndrome typically present with fully developed female external genitalia and absence or rudimentary derivatives of the Wolffian duct system [4]. As described by J. Morris, a blind-ending vagina and the presence of testes in the abdominal or inguinal region are almost always observed [7].

Feminization with the development of secondary sexual characteristics may be associated with aromatization of testosterone into estrogen. However, due to the absence of androgen action, patients typically exhibit sparse axillary and pubic hair growth [9]. The female phenotype also results from intrauterine estrogenization, which may stem from endogenous (maternal androgens, hormone-producing tumors) or exogenous (progestin intake) stimulation [12], and is further enhanced in the absence of testosterone and dihydrotestosterone effects on target organs. Phenotypic females typically first present to pediatric gynecologists during puberty due to primary amenorrhea [9]. The testes may be detected during imaging studies and misinterpreted as cysts or other pathological masses. When located in the inguinal canal, they are frequently mistaken for inguinal hernias, often bilateral. In some cases, parents consult pediatric surgeons for elective repair of inguinal hernias [3, 4, 9]. In the absence of orchiectomy, malignant transformation may occur [2, 3].

To date, over 1100 different pathogenic variants have been identified in the AR gene, including deletions, duplications, insertions, and point mutations, the majority of which are missense pathogenic variants [4, 13].

We present a familial case of Morris syndrome involving a previously undescribed AR gene mutation (NM_001011645.3). The parents are not consanguineous. The mother is 156.5 cm tall, with menarche at age 13–14; initial oligomenorrhea was followed by normalization of the menstrual cycle. She has no history of endocrine disorders or infertility. The father is 164 cm tall and has no known endocrine disorders. The patients are not citizens of the Russian Federation, which contributed to delayed and incomplete preventive specialist evaluations and lack of regular medical follow-up. The family includes three daughters and one son. The middle daughter and the son are healthy.

CASE DESCRIPTIONS

Case report No. 1

A 14-year-old girl (the eldest daughter) was admitted to the pediatric surgery department of a city children’s hospital for elective hernioplasty for bilateral inguinal hernias.

Medical history. The patient was born from the first pregnancy, which was complicated by maternal preeclampsia and anemia. It was the mother’s first delivery, post-term (after 40 weeks of gestation) and spontaneous. Birth weight was 3000 g, length 50 cm, Apgar score 7/8. In early childhood, the patient had rickets and intracranial hypertension. No history of endocrine disorders. The patient was under regular follow-up by an orthopedic traumatologist for scoliosis and pectus excavatum, an urologist for bilateral inguinal hernias, and a pediatrician for biliary dyskinesia.

History of present illness. Since early childhood, the patient had been followed by an urologist for bilateral inguinal hernia (bulging in the inguinal folds). Elective surgery was performed on July 6, 2022, during which oval-shaped structures resembling testes were found in the hernial sac. A biopsy was performed. The gonads were repositioned into the abdominal cavity, and bilateral inguinal canal repair was completed. Histological examination revealed testicular tissue in the maturation stage (Figure 1).

 

Fig. 1. Maturing testicular tissue revealed by histological examination, hematoxylin and eosin staining.

Рис. 1. Ткань яичка в стадии созревания, выявлена при гистологическом исследовании, окраска гематоксилином и эозином.

 

Based on these findings, further inpatient evaluation was performed. Pelvic ultrasound revealed a vaginal remnant in the form of a fibrous band and absence of the cervix and uterus. Testicular dimensions were measured as follows: right testis, 3.2 × 2.4 × 2.7 cm, without follicular apparatus; left testis, 3.0 × 2.3 × 3.2 cm, without follicular apparatus. The patient was discharged to outpatient care and referred to a geneticist for karyotyping, after which a second-stage surgery—gonadectomy—was planned.

Physical examination. Height 155 cm (−0.69 SDS), weight 34.5 kg (−2.75 SDS), body mass index 14.33 (−2.31 SDS). The general condition was satisfactory; the patient plays football. She has an asthenic body build. Academically, she performs well, with intellectual development appropriate for her age. Signs of connective tissue dysplasia were observed (hyperextension of the elbow joints, hypotonia), along with scoliosis and pectus excavatum. According to the pediatric endocrinologist, sexual development was classified as Tanner stage II: Ma II–III, A I, P I–II, Me (–), clitoris of normal size, and female-type external genitalia.

A sex chromatin test performed on August 3, 2022, was negative. Karyotyping on August 4, 2022, showed 46,XY, interpreted by the geneticist as a balanced male karyotype with sex reversal. On November 7, 2022, sequencing was performed at the Medical Genetic Center of St. Petersburg using the Illumina platform with paired-end sequencing (2 × 150 bp). The average coverage depth was 245.53×, with 99.95% of targeted nucleotides covered at >10× depth. A previously unreported hemizygous AR gene variant was identified in exon 7: HG38, chrX: 67721856T>C, c.746T>C, resulting in an amino acid substitution (p.Met249Thr) with a coverage depth of 100×. This variant is located in a conserved region.

Laboratory evaluation of hormonal activity revealed the following: anti-Müllerian hormone 93 ng/mL (<12.6), inhibin B 334.1 pg/mL (<83.0), follicle-stimulating hormone (FSH) 1.69 mIU/mL (0.95–11.95), and testosterone 2.3 nmol/L (0.36–1.54). Bone age based on wrist joints radiographs corresponded to 14 years. Sanger sequencing confirmed that the variant was inherited from the mother. Thus, androgen insensitivity syndrome with 46,XY, AR c.746T>C (p.Met249Thr) was diagnosed.

Additional DNA sequencing of parental and sibling samples was performed. Using paired-end sequencing (2 × 150 bp) on the Illumina platform, a variant in exon 7 of the AR gene, HG38, chrX:67721856T>C, c.746T>C, resulting in an amino acid substitution (p.Met249Thr), was identified in the mother’s sample in the heterozygous state. The same mutation was detected in the biological material of the younger sister (described in Clinical сase No. 2). No pathogenic variants were identified in the biological samples of the proband’s father, brother, or middle sister during sequencing. Thus, a pedigree was constructed for the sister and her relatives (Figure 2).

 

Fig. 2. Genealogic tree of the patients.

Рис. 2. Генеалогическое дерево пациентов.

 

After additional evaluation, consultations with a pediatric endocrinologist and geneticist, and parental consent, repeat surgery was performed on January 18, 2023, consisting of bilateral laparoscopic gonadectomy and right inguinal canal revision. Macroscopically, testes was identified (Figure 3).

 

Fig. 3. Gross specimen of the testes.

Рис. 3. Макропрепарат тестикул.

 

Histological examination confirmed the initial morphological diagnosis. The child was discharged for outpatient follow-up with a pediatric surgeon, pediatric endocrinologist, and psychologist.

Case report No. 2

A 6-year 10-month-old girl was admitted to the surgical department of a city children’s hospital for hernioplasty for bilateral inguinal hernia.

Medical history. The child was born of the fourth pregnancy, which was complicated by an acute respiratory infection of unspecified etiology in the mother. The mother’s first pregnancy resulted in the birth of a girl with Morris syndrome (diagnosed concurrently); the second, a healthy boy (11 years 9 months old); the third, a healthy girl (9 years 7 months old). The fourth delivery was full-term and spontaneous. Birth weight was 3200 g, length 54 cm, Apgar score 8/9. In early childhood, the patient had rickets. Currently, she is growing and developing according to her age, fully vaccinated, and is under follow-up by an orthopedic traumatologist with a diagnosis of «poor posture.»

History of present illness. Since early childhood, the patient had been under follow-up by a pediatric urologist for bilateral inguinal hernia. Elective surgery was performed on July 6, 2022. During the operation, testes were found within the hernia sac; biopsy was performed, the testes were repositioned into the abdominal cavity, and bilateral hernioplasty was completed. Histological examination of the superficial biopsy revealed only tunica albuginea without gonadal tissue. In light of these histology findings and similar results obtained from a histologic examination of the biopsy specimen of the elder sister, further evaluation was undertaken. Pelvic ultrasound revealed a vaginal remnant in the form of a fibrous band measuring 1.6 × 0.6 cm and absence of the cervix and uterus. Testicular dimensions were measured as follows: right testis 2.2 × 1.5 × 1.7 cm, without follicular apparatus; left testis 2.3 × 1.6 × 1.9 cm, without follicular apparatus. The patient was discharged for outpatient follow-up and referred to a geneticist for karyotyping; based on the karyotype results, a second-stage surgery—gonadectomy—was planned.

Physical examination. Height 119 cm (–0.25 SDS), weight 20.0 kg (–0.68 SDS), BMI 14.12 (–0.85 SDS). The general condition was satisfactory; the girl shows interest in drawing, is learning to read and write, and demonstrates normal intellectual development. Asthenic body type, sluggish. Signs of connective tissue dysplasia (elbow joint hyperextension) were noted. According to a pediatric endocrinologist, pubertal development was Tanner: pub I, external genitalia were female in appearance.

Karyotyping on August 30, 2022, showed 46,XY, interpreted by the geneticist as a balanced male karyotype with sex reversal. On October 21, 2022, sequencing was performed at the Medical Genetic Center of St. Petersburg using the Illumina platform with paired-end sequencing (2 × 150 bp). The average coverage depth was 277.53×, with 99.96% of targeted nucleotides covered at >10× depth. A previously unreported hemizygous AR gene variant was identified in exon 7: HG38, chrX: 67721856T>C, c.746T>C, resulting in an amino acid substitution (p.Met249Thr) with a coverage depth of 147×. This variant is located in a conserved region. Laboratory evaluation of hormonal activity revealed the following: anti-Müllerian hormone 116 ng/mL (<8.9), inhibin B 228.5 pg/mL (<83.0), FSH 2.7 mIU/mL (0.95–11.95), and testosterone 0.6 nmol/L (0.36–1.54). Bone age based on wrist joints radiographs corresponded to age 6 years. Sanger sequencing confirmed that the variant was inherited from the mother. Thus, androgen insensitivity syndrome with 46,XY, AR c.746T>C (p.Met249Thr) was diagnosed.

On January 18, 2023, with parental consent, bilateral laparoscopic gonadectomy with subsequent hernioplasty was performed as planned. The child was discharged under outpatient follow-up by a pediatric endocrinologist, pediatric surgeon, and psychologist.

DISCUSSION

Complete androgen insensitivity is more commonly diagnosed in cases with a positive family history, and less frequently during prenatal karyotyping of a fetus with a female phenotype, in girls with inguinal hernias, or in adolescent girls presenting with primary amenorrhea [3, 14, 15]. The endocrine profile of patients is altered, and the degree of alteration depends on the level of androgen insensitivity. An elevated or normal basal serum testosterone concentration is typically observed, along with high levels of luteinizing hormone [3]. This reflects impaired negative feedback regulation between androgens and the anterior pituitary. During puberty, an increase in testosterone levels is observed due to luteinizing hormone stimulation of steroid production by Leydig cells [16]. In the presented cases, the first patient, aged 14 years at the time of examination, had a serum testosterone concentration 1.5 times above the reference values and was 2.3 nmol/L, whereas the 6-year-10-month-old patient, who had not yet entered puberty, showed testosterone levels within the normal range.

Inhibin B, synthesized by Sertoli cells in the seminiferous tubules of the testes and in ovarian follicles, regulates FSH secretion [15]. The elevated levels of inhibin B detected in both patients indicate preserved hormonal regulatory and spermatogenic functions of testicular tissue. In patients with CAIS, FSH levels do not exceed reference values because gonadal inhibin regulates FSH biosynthesis [3]. In both cases presented, FSH concentrations were within the normal range.

In response to FSH stimulation, Sertoli cells synthesize anti-Müllerian hormone, which induces regression of Müllerian duct derivatives in males [16]. Elevated anti-Müllerian hormone levels in both cases indicate absence of development of functional female reproductive organ.

The prevalence of inguinal hernia in the pediatric population is approximately 1–4%, with a 10 : 1 male-to-female ratio; the presence of inguinal hernia in phenotypic girls—especially bilateral hernia—represents an important diagnostic clue [17]. Upon such findings, prior to deciding on hernioplasty, additional routine examinations such as pelvic ultrasound or magnetic resonance imaging of the pelvic organs and hernia contents should be performed. If necessary, karyotyping or gonadal biopsy with subsequent histological analysis should also be conducted [18].

Management of patients with Morris syndrome involves addressing medical, social, and gender-related issues and requires a multidisciplinary approach [14, 19]. Surgeons are often the first to suspect or discover testicular tissue within a hernial sac, particularly in cases with insufficient preoperative evaluation [20]. When determining the true karyotype to guide therapeutic decision-making, several factors must be considered. On the one hand, the patient’s age is important, as the endogenous hormonal milieu has a beneficial effect on the development of secondary sex characteristics [21]. On the other hand, the ectopic position of the testes increases the risk of malignancy, providing a rationale for surgical intervention [14, 22]. It should be noted that in early childhood and before puberty, the risk of tumor transformation is approximately 0.8%–2.0% [23, 24], but it increases with age, reaching up to 33% by 55 years [10]. In patients with CAIS, delaying orchiectomy until late adolescence allows for the development of a female phenotype and increased muscle mass through aromatization of androgens to estrogens [14, 22, 24]. After gonadectomy, patients require estrogen replacement therapy to induce or maintain pubertal development [12, 14]. In addition, estrogen therapy helps prevent osteoporosis [19]. In patients with PAIS or MAIS, gonadectomy and genital reconstructive surgery should be performed before puberty due to the high likelihood of virilization. Combined with psychological support, this approach helps avoid or minimize psychosomatic disorders [10, 14].

In the present cases, treatment strategies were guided not only by medical but also psychosocial considerations. On the one hand, performing gonadectomy during reproductive system development (case 1) or before puberty (case 2) may cause a number of complications described above. However, in the first case, timely removal of the gonads reduced virilization. On the other hand, to induce female puberty postoperatively, estrogen replacement therapy was initiated under the supervision of a pediatric endocrinologist.

CONCLUSION

Physicians should maintain a high index of suspicion when diagnosing bilateral inguinal hernia in girls. Particular emphasis should be placed on the roles of neonatologists, pediatricians, and pediatric surgeons. When planning preoperative evaluation, it is important to clarify the likely contents of the hernia sacs; if there is uncertainty, imaging of the pelvic organs should be performed to determine both the hernia contents and, when risk factors are present, the anatomy of the reproductive system. Suspected androgen insensitivity syndrome requires genetic confirmation. Decisions regarding the timing of surgical intervention should be based not only on clinical indications but also on the role of estrogens in the child’s development. Patients with Morris syndrome require a comprehensive multidisciplinary approach to treatment and rehabilitation.

ADDITIONAL INFO

Authors’ contribution: M.M. Al-Hares, V.Yu. Tamaev: supervision and surgical treatment of the patient, preparation and writing of the article; G.A. Mikhailov, I.A. Lisitsa: collection and analysis of literary sources, writing and editing of the article; A.N. Zavyalova: advisory assistance, literature review, editing the article; O.V. Lisovskii, D.O. Ivanov: development of the concept and structure of the article, text editing, final editing of the article. All authors have approved the publication version and also agreed to be responsible for all aspects of the each part of the work and ensured reliable consideration of the issues related to the accuracy and integrity.

Consent for publication: The authors obtained written informed voluntary consent of the patient’s legal representatives to publish personal data, including photographs, in a scientific journal, including its electronic version. The scope of the published data was agreed with the patient’s legal representatives.

Funding sources: No funding.

Disclosure of interests: The authors declare no relationships, activities, or conflicts of interest with any third parties (commercial or non-commercial) that could have influenced the content of this article within the past three years.

Statement of originality: The authors did not use any previously published material (text, illustrations, or data).

Data availability statement: All data obtained in the present study are available in the article.

Generative AI: No generative AI technologies were used.

Provenance and peer-review: This paper was submitted to the journal on an initiative basis and reviewed according to the usual procedure. Two external reviewers, a member of the editorial board and invited by the editorial board as specialists on the topic of the article.

About the authors

Milad M. Al-Hares

Saint Petersburg State Pediatric Medical University; Filatov Children’s Hospital

Email: haresmilad@gmail.com
ORCID iD: 0000-0002-4765-5421
SPIN-code: 3485-1655
Russian Federation, Saint Petersburg; Saint Petersburg

Vadim Yu. Tomaev

Filatov Children’s Hospital

Email: hirurg.tomaev@mail.ru
ORCID iD: 0009-0004-4228-5849
Russian Federation, Saint Petersburg

Gleb A. Mikhaylov

Filatov Children’s Hospital

Email: mihailov.g@db5.ru
ORCID iD: 0000-0001-9073-6975
Russian Federation, Saint Petersburg

Ivan A. Lisitsa

Saint Petersburg State Pediatric Medical University

Author for correspondence.
Email: ivan_lisitsa@mail.ru
ORCID iD: 0000-0003-3501-9660
SPIN-code: 4937-7071
Russian Federation, Saint Petersburg

Oleg V. Lisovsky

Saint Petersburg State Pediatric Medical University

Email: oleg.lisowsky@yandex.ru
ORCID iD: 0000-0002-1749-169X
SPIN-code: 7510-5554

MD, Cand. Sci. (Medicine)

Russian Federation, Saint Petersburg

Anna N. Zavyalova

Saint Petersburg State Pediatric Medical University

Email: anzavjalova@mail.ru
ORCID iD: 0000-0002-9532-9698
SPIN-code: 3817-8267

MD, Dr. Sci. (Medicine)

Russian Federation, Saint Petersburg

Dmitry O. Ivanov

Saint Petersburg State Pediatric Medical University

Email: spb@gpma.ru
ORCID iD: 0000-0002-0060-4168
SPIN-code: 4437-9626

MD, Dr. Sci. (Medicine)

Russian Federation, Saint Petersburg

References

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