LIM Homeodomain (LIM-HD) Genes and Their Co-Regulators in Developing Reproductive System and Disorders of Sex Development

LIM homeodomain (LIM-HD) family genes are transcription factors that play crucial roles in a variety of functions during embryonic development. The activities of the LIM-HD proteins are regulated by the co-regulators LIM only (LMO) and LIM domain-binding (LDB). In the mouse genome, there are 13 LIM-HD genes (<i>Lhx1</i>–<i>Lhx9</i>, <i>Isl1</i>–<i>2</i>, <i>Lmx1a</i>–<i>1b</i>), 4 Lmo genes (<i>Lmo1</i>–<i>4</i>), and 2 Ldb genes (<i>Ldb1</i>–<i>2</i>). Amongst these, <i>Lhx1</i> is required for the development of the müllerian duct epithelium and the timing of the primordial germ cell migration. <i>Lhx8</i> is necessary for oocyte differentiation and <i>Lhx9</i> for somatic cell proliferation in the genital ridges and control of testosterone production in the Leydig cells. <i>Lmo4</i> is involved in Sertoli cell differentiation. Mutations in <i>LHX1</i> are associated with müllerian agenesis or Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. <i>LHX9</i> gene variants are reported in cases with disorders of sex development (DSD). Mutations in <i>LHX3</i> and <i>LHX4</i> are reported in patients with combined pituitary hormone deficiency having absent or delayed puberty. A transcript map of the <i>Lhx</i>, <i>Lmo,</i> and <i>Ldb</i> genes reveal that multiple LIM-HD genes and their co-regulators are expressed in a sexually dimorphic pattern in the developing mouse gonads. Unraveling the roles of LIM-HD genes during development will aid in our understanding of the causes of DSD.

ANDROGEN INSENSITIVITY SYNDROME – A CASE REPORT

Background: AIS is one of the most commonly diagnosed XY DSD, with an estimated prevalence of 2:100.000 to 5:100.0001 and an incidence of 1:20.0002 to 1:99.0003. The name testicular feminization syndrome was coined by John McLean Morris of Yale University in 1953. The first description of this syndrome dates back to 1817, as quoted by Morris 4. It is the third most common cause of primary amenorrhea after gonadal dysgenesis and Mullerian agenesis 5. Case Report and Discussion: A 15-year-old phenotypic girl was evaluated for primary amenorrhea to find Complete Androgen Insensitivity Syndrome (CAIS) and underwent bilateral orchidectomy with plan for vaginoplasty at AIMSR, Hyderabad. Review of Literature: The treatment of AIS is based on the reinforcement sexual identity, gender identity plan and hormone replacement therapy. The prognosis is good, if the testicular tissue is resected at proper time. Conclusion: CAIS should be considered as important differential diagnosis in delayed menarche while evaluation for primary amenorrhea and early gonadectomy can avoid gender identity disorder (GID) / psychological issues Keywords: CAIS, GID

An Unusual Cause of Primary Amenorrhea

Background: Müllerian agenesis is the most common cause of primary amenorrhea in patients with typical thelarche and adrenarche. Most of the time, this diagnosis is made at the age of 10-13 years. Clinical Case: We present a case of a 18 year-old Vietnamese female who was referred to the endocrine clinic for primary amenorrhea. She stated that pubic hair developed at age 15 years. Patient is sexually active and uses condoms. She has 10 siblings (7 sisters, 3 brothers), 6 older sisters with menarche at ages 12-16 and a younger sister of 10 years old who has not yet had menarche. In addition, her older sister has 3 biological children and there was no reported infertility in her family. She stated that a pelvic ultrasound had been done at age of 17 years that showed no uterus. Oral contraceptives had been previously trialed and failed to induce withdrawal bleeding. HT 157.48 cm, WT 55.34 kg. The patient had a normal female phenotype with normal bilateral breast development, and no hirsutism. She was not concerned with this issue, which questioned her personality and coping skills. Laboratory testing-cortisol 13.0 ug/dL (5.3- 2.5), ACTH 29 pg/mL (0-47), estradiol 46.04 pg/mL), total testosterone 39 ng/dL (2-45), free testosterone 4.2 pg/mL (0.1-6.4), TSH 1.80 uIU/mL (0.358- .74), free T4 0.99 ng/dL(0.76- .46), FSH 4.4 mIU/mL (Follicular Phase:2.3 - 12.6, Midcycle Peak:5.2-17.5 mIU/mL, Luteal Phase:1.7-12.9 mIU/mL), Progesterone &lt;0.5 ng/mL (follicular -less than 0.8 ng/ml, luteal=4.1- 3.7 ng/ml, mid-luteal= 4.5-25.2 ng/ml), LH 3.7 mIU/mL (follicular phase = 1.9-26.2 mIU/mL, Midcycle = 22.8 - 6.1 mIU/mL, Luteal phase = 0.6-16.6 mIU/mL). Transvaginal ultrasound-uterus not visualized; ovaries were unremarkable. DXA scan-normal Z scores. She refused to have a karyotype analysis. Differential diagnoses included müllerian agenesis, 5-alpha-reductase deficiency and complete androgen insensitivity syndrome. Unfortunately, our patient declined karyotype testing. Based on clinical presentation, which showed normal female genitalia, absence of uterus and normal laboratory finding, the most likely diagnosis was müllerian agenesis (Mayesr-Rokitansky-Kuster-Hauser syndrome). This syndrome has an incidence of 1/4,500-5,000 females and is caused is caused by embryologic underdevelopment of the müllerian duct, with resultant agenesis or atresia of the vagina, uterus, or both. Patients with müllerian agenesis usually are identified when they are evaluated for primary amenorrhea with otherwise typical growth and pubertal development, as in our patient. Psychosocial and genetic counseling, as well as offering options for pregnancy are important. In addition, certain personality traits, such as higher neuroticism, depression, and decreased coping styles may be observed. References: Obstetrics and Gynecology, Müllerian agenesis: Diagnosis, management, and treatment. Vol.131, NO.1, January 2018

Pituitary Stalk Interruption Syndrome in a 40-Year-Old Female With Absent Uterus and Ovaries

Background: A patient with multiple pituitary hormone deficiencies due to a rare congenital pituitary defect also presented with an absent uterus and ovaries. Coexisting Müllerian agenesis was suspected, however hormone replacement unraveled a different story. Case Presentation: A 40-year-old female presented with generalized body weakness and euvolemic hyponatremia. She also had cold intolerance, constipation, primary amenorrhea and dyspareunia. As a child, she was worked up for short stature but was lost to follow up. Physical examination showed Tanner stage 1 breast and pubic hair, and absence of axillary hair. She had no facial anomalies, visual abnormalities or anosmia. Hormone panel was consistent with panhypopituitarism: ACTH 5.69 pg/mL (&lt;46 pg/mL), cortisol 1.9 ug/dL (4.30-22.40 μg/dL), TSH 3.375 uIU/mL (0.55-4.78 uIU/mL), FT4 0.51 ng/dL (0.55-4.78 uIU/mL), FT3 1.79 pg/mL (2.30-4.20 pg/mL), LH &lt;0.07 mIU/mL (1.9-12.5 mIU/mL), FSH 0.95 mIU/mL (2.5-10.2 mIU/mL) and IGF-1 40.8 ng/dL (109-284 ng/mL). Bone age was delayed (16-year-old) but with most ossification centers fused. Pituitary MRI showed hypoplastic anterior pituitary, ectopic posterior pituitary and absent pituitary stalk suggestive of Pituitary Stalk Interruption Syndrome (PSIS). Low estradiol 19.35 pg/mL (19.5-144.2 pg/mL) in the setting of low LH and FSH was compatible with hypogonadotrophic hypogonadism. She had female-range serum testosterone level &lt;0.007 ng/mL (0.1209-0.5946 ng/mL) and karyotype of 46XX. Transvaginal ultrasound revealed a blind vaginal pouch with absent uterus, fallopian tubes and ovaries; hence Müllerian agenesis was also considered. Hormonal replacement with prednisone, levothyroxine and conjugated equine estrogen was started. Secondary osteoporosis was treated with alendronate, calcium and vitamin D on top of estrogen therapy. Six months after initiation of estrogen, there was appearance of a small anteverted uterus and atrophic right ovary. Müllerian agenesis was ruled out and hypogonadotropic hypogonadism was proved to be the cause of the initial absence of the uterus and ovaries on imaging. Conclusion: Increased awareness of PSIS is important since early and accurate diagnosis is crucial for timely initiation of hormone replacement. This case also demonstrates the need for reassessment after hormonal replacement in patients with severe estrogen deficiency and apparent Müllerian agenesis.

Clinical and Radiological Findings in Mayer-Rokitansky-Küster-Hauser Syndrome type 2

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) or (Müllerian Agenesis) represents uterovaginal aplasia or hypoplasia of unknown etiology in young women with usual 46, XX karyotype, and normal secondary sexual characteristics. We report a 15-year-old adolescent woman with primary amenorrhea, and normal pubertal secondary sexual characteristics, normal hormonal workup, and clinical examination. Abdominopelvic magnetic resonance imaging (MRI) revealed cervical and uterine agenesis, with the absence of the proximal thirds of the vagina. Both kidneys are fused in the right iliac fossa with oval lobulated appearance, picture of crossed fused ectopia. The ovaries are normal and located bilaterally. The diagnosis of MRKHS type 2 was confirmed based on clinical, biochemical, and radiological findings. The correct clinical and radiological diagnosis of MRKHS by MRI is crucial for the next steps in long-term management. Keywords: Müllerian Agenesis, Uterovaginal malformations.

Single perineal opening with ‘H-type’ cecovesical fistula and blind-ending foreshortened distal colon: a new variant of persistent cloaca

Persistent cloaca is a rare and severe variety of anorectal malformation, which is more common in females and includes a spectrum of abnormalities. The urinary tract, genital tract and rectum open into a common channel, which exteriorises as a single perineal opening. We are reporting a patient with a novel variation in the classical anatomy of the cloaca. The child has a short blind-ending colon with a cecovesical fistula associated with mullerian agenesis and lipomyelomeningocoele. The child is being managed in a stepwise approach and she has completed the anal reconstruction. Here, we discuss this novel variation in anatomy and challenges in its management.

Aetiological analysis of primary amenorrhea: a retrospective study

Background: Primary amenorrhea is defined as the failure to reach menarche. Primary amenorrhea is the lack of menses by age 15 with secondary sex characteristics, or at 13 with absence of secondary sex characteristics. Objective was to determine various etiological factors of primary amenorrhea in Gynecological practice.Methods: A retrospective study was conducted in a Gynae clinic in Shivpuri and a Maternity hospital in Gwalior from January 2015 to December 2019. Results: A total of 57 of the patients were evaluated in the study period. Most of the patients were unmarried adolescent girls (71.92%). The most common presenting symptom was, not attained menarche (36.84%). Based on the presence or absence of breast and uterus: group, I – breast present and uterus present 13 cases (22.77%), group II - breast present and uterus absent 26 cases (45.61%), group III - breast absent and uterus present 17cases (29.79%), group IV - breast absent and uterus absent 1 case (1.75%) were present. The most common etiological factors were Mullerian Agenesis 22 cases (38.60%) and Gonadal dysgenesis 7 cases (12.28%). (56.14 %) cases were normogonadotropic, followed by (15.78%) cases were of Hypergonadotropic hypogonadism, (14.03%) hypogonotropic hypogonadism and (14.03%) were of hyperendrogenism and others causes. In cases of Mullerian abnormalities, in findings of renal ultrasound or IVP (72.72%) cases were normal.Conclusions: The most common etiological factors of primary amenorrhea were Mullerian Agenesis. Amenorrhea is a common problem encountered by the primary care physician. A thorough history and clinical examination are needed for differential diagnosis.