What is agenesis

Agenesis is a medical term that refers to the failure of an organ to develop during embryonic growth and development due to the absence of primordial tissue.

Many forms of agenesis are referred to by individual names, depending on the organ affected:

• Agenesis of the corpus callosum – failure of the Corpus callosum to develop
• Agenesis of kidney – failure of one or both of the kidneys to develop
• Amelia – failure of the arms or legs to develop
• Dental agenesis – tooth agenesis or hypodontia is one of the most common anomalies of the human dentition, characterized by the developmental absence of one or more teeth.
• Penile agenesis – failure of penis to develop
• Müllerian agenesis – failure of the uterus and part of the vagina to develop
• Agenesis of the gallbladder – failure of the Gallbladder to develop. A person may not realize they have this condition unless they undergo surgery or medical imaging, since the gallbladder is neither externally visible nor essential.

Agenesis of the corpus callosum

Agenesis of the corpus callosum is a rare disorder that is present at birth (congenital). Agenesis of the corpus callosum is characterized by a partial or complete absence (agenesis) of the corpus callosum, the structure that connects the two hemispheres (left and right) of the brain. This part of the brain is normally composed of transverse fibers. Current research suggests that as many as 7 in 1000 to 1 person in 3,000 is affected by some disorder of the corpus callosum. The rate of diagnosis of these disorders is likely to increase with greater access to the brain scanning technology such as ultrasound, CT or MRI scan.

In a typical infant brain, the corpus callosum develops between 12 to 16 weeks after conception (near the end of the first trimester). While the entire structure develops prior to birth, the fibers of the corpus callosum continue to become more and more effective and efficient on into adolescence. By the time a child is approximately 12 years of age, the corpus callosum functions essentially as it will in adulthood, allowing rapid interaction between the two sides of the brain. From this age on (and typically earlier) as the corpus callosum becomes increasingly functional in their typically developing peers, children with agenesis of the corpus callosum appear to fall behind developmentally because the corpus callosum is absent.

Parents often ask if the corpus callosum is the only path between the hemispheres of the brain. It isn’t the only path, but it is by far the most important. Some much smaller connections are usually present in corpus callosum disorders. The anterior commissure is the largest and most useful of these other pathways. However, it only has about 50,000 nerve fibers, a far cry from the more than 200 million fibers in the corpus callosum.

Agenesis of the corpus callosum can occur as an isolated condition or in combination with other cerebral abnormalities, including Arnold-Chiari malformation, Dandy-Walker syndrome, schizencephaly (clefts or deep divisions in brain tissue), and holoprosencephaly (failure of the forebrain to divide into lobes.) Girls may have a gender-specific condition called Aicardi syndrome, which causes severe cognitive impairment and developmental delays, seizures, abnormalities in the vertebra of the spine, and lesions on the retina of the eye. Agenesis of the corpus callosum can also be associated with malformations in other parts of the body, such as midline facial defects. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. Children with the most severe brain malformations may have intellectual impairment, seizures, hydrocephalus, and spasticity. Other disorders of the corpus callosum include dysgenesis, in which the corpus callosum is developed in a malformed or incomplete way, and hypoplasia, in which the corpus callosum is thinner than usual. Individuals with these disorders have a higher risk of hearing deficits and cardiac abnormalities than individuals with the normal structure. Impairments in social interaction and communication in individuals having a disorder of the corpus callosum may overlap with autism spectrum disorder behaviors. It is estimated that at least one in 4,000 individuals has a disorder of the corpus callosum.

The cause of agenesis of corpus callosum is usually not known, but it can be inherited as either an autosomal recessive trait or an X-linked dominant trait. Agenesis of the corpus callosum can also be caused by an infection or injury during the twelfth to the twenty-second week of pregnancy (intrauterine) leading to developmental disturbance of the fetal brain. Intrauterine exposure to alcohol (fetal alcohol syndrome) can also result in agenesis of the corpus callosum. In some cases mental retardation may result, but intelligence may be only mildly impaired and subtle psychosocial symptoms may be present.

Agenesis of the corpus callosum may also be identified during pregnancy through an ultrasound. Agenesis of the corpus callosum is frequently diagnosed during the first two years of life. An epileptic seizure can be the first symptom indicating that a child should be tested for a brain dysfunction. Agenesis of the corpus callosum can also be without apparent symptoms in the mildest cases for many years.

Physically, complete agenesis of the corpus callosum is a condition that does not change. It will not get worse. Since the corpus callosum is already absent, it cannot regenerate or degenerate. Likewise, in partial agenesis of the corpus callosum and hypoplasia, once the infant’s brain is developed, no new callosal fibers will emerge.

In that sense, disorders of the corpus callosum are conditions one must “learn to live with” rather than “hope to recover from”. Long-term challenges are associated with malformation of the corpus callosum, but this in no way suggests that individuals with disorder of the corpus callosum cannot lead productive and meaningful lives.

Agenesis of the corpus callosum types

Complete agenesis of the corpus callosum

If the nerve fibers don’t cross between the hemispheres during that critical prenatal time, they never will. agenesis of the corpus callosum becomes a permanent feature of the individual’s brain. The callosal fibers may have started to grow, but when unable to cross between the hemispheres, they grow toward the back of the same hemisphere where they began. These fibers form what are called Bundles of Probst. Some smaller connections between the hemispheres develop in most individuals with agenesis of the corpus callosum. These are the anterior commissure, posterior commissure, and hippocampal commissure. However, each of these is at least 40,000 times smaller than the corpus callosum. Thus, they cannot compensate completely for the absence of the corpus callosum.

Partial agenesis of the corpus callosum

In partial agenesis of the corpus callosum, the corpus callosum began to develop, but something stopped it from continuing. Since the corpus callosum develops from front to back, the part of the corpus callosum that is present in partial agenesis of the corpus callosum usually will be toward the front of the brain, with the back portion missing. Partial agenesis of the corpus callosum includes the entire range of partial absence, from absence of only a small portion of callosal fibers to absence of most of the corpus callosum. In partial agenesis of the corpus callosum, the other smaller commissures usually are present.

Hypoplasia of the corpus callosum

Hypoplasia refers to a thin corpus callosum. On a mid-line view of the brain, the structure may extend through the entire area front-to-back as would a typical corpus callosum, but it looks notably thinner. It is unclear in this case if the callosal nerve fibers are fully functional and just limited in number, or if they are both less plentiful and more dysfunctional.

Dysgenesis of the corpus callosum

Dysgenesis means that the corpus callosum developed, but developed in some incomplete or malformed way. Thus, partial agenesis of the corpus callosum and hypoplasia of the corpus callosum would be forms of dysgenesis, as would any other form of inadequate callosal development. Dysgenesis is a broad term for any malformation of the corpus callosum that is not a complete absence (agenesis).

Agenesis of the corpus callosum causes

The disruptions to the development of the corpus callosum occur during the 5th to 16th week of pregnancy. In most cases, the cause of agenesis of the corpus callosum is unknown. There is no single cause and many different factors can interfere with this development, including:

• Prenatal infections or viruses (for example, rubella)
• Chromosomal (genetic) abnormalities (for example, trisomy 8 and 18, Andermann syndrome, and Aicardi syndrome)
• Toxic metabolic conditions (for example, Fetal Alcohol Syndrome)
• Blockage of the growth of the corpus callosum (for example, cysts)

Disorders of the corpus callosum are not illnesses or diseases, but abnormalities of brain structure. Many people with these conditions are healthy. However, other individuals with disorders of the corpus callosum do require medical intervention due to seizures and/or other medical problems they have in addition to the disorder of the corpus callosum.

Agenesis of the corpus callosum can also be inherited as an autosomal recessive trait or an X-linked dominant trait. Agenesis of the corpus callosum may also be due in part to an infection during pregnancy (intrauterine) leading to abnormal development of the fetal brain.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

In X-linked dominant disorders, a female with only one X chromosome with an abnormal gene will develop the disease. However, the affected male always has a more severe condition. Sometimes, affected males die before birth so that only female patients survive. This seems to be true for one form of agenesis of corpus callosum known as Aicardi syndrome. The majority of patients diagnosed so far have been females. Aicardi syndrome has been seen occasionally in males with an extra X chromosome.

Can agenesis of the corpus callosum be cured?

Stem-cell research has raised expectations and hopes that scientists may find “cures” for some forms of nervous system damage and developmental abnormalities. At this time, it does not seem likely that agenesis of the corpus callosum will be impacted by such interventions. This is due to the large number of steps in the process of development of the corpus callosum that would need to be re-instituted. Another factor is that the brain already has organized without the corpus callosum. Overall, agenesis of the corpus callosum are conditions one must “learn to live with” rather than “hope to recover from.” Long-term challenges are associated with absence of the corpus callosum, but this in no way suggests that individuals with disorder of the corpus callosum cannot lead productive and meaningful lives.

Will agenesis of the corpus callosum get worse?

Physically, callosal agenesis and hypoplasia are conditions that do not change. Once the infant’s brain is developed, no new callosal fibers will emerge. Nor will the existing callosal fibers degenerate, unless an individual gets an additional degenerative neurological condition.

Behaviorally, however, individuals with disorder of the corpus callosum may fall behind their peers in social and problem solving skills in elementary school or as they approach adolescence. In typical development, the fibers of the corpus callosum become more efficient as children approach adolescence. At that point children with an intact corpus callosum show rapid gains in abstract reasoning, problem solving, and social comprehension. Although a child with disorder of the corpus callosum may have kept up with his or her peers until this age, as the peer-group begins to make use of an increasingly efficient corpus callosum, the child with disorder of the corpus callosum falls behind in mental and social functioning. In this way, the behavioral challenges for individuals with disorder of the corpus callosum may become more evident as they grow older.

Agenesis of the corpus callosum symptoms

Agenesis of the corpus callosum produces symptoms during the first two years of life in approximately ninety percent of those affected.

Agenesis of the corpus callosum may initially become evident through the onset of epileptic seizures during the first weeks of life or within the first two years. However, not all individuals with agenesis of the corpus callosum have seizures. Other symptoms that may begin early in life are feeding problems and delays in holding the head erect. Sitting, standing and walking may also be delayed. Impairment of mental and physical development, and/or an accumulation of fluid in the skull (hydrocephalus) are also symptomatic of the early onset type of this disorder.

Non-progressive mental retardation, impaired hand-eye coordination and visual or auditory (hearing) memory impairment can be diagnosed through neurological testing of patients with agenesis of the corpus callosum.

In some mild cases, symptoms may not appear for many years. Older patients are usually diagnosed during tests for symptoms such as seizures, monotonous or repetitive speech, or headaches. In mild cases it may be overlooked due to lack of obvious symptoms during childhood.

Some patients may have deep-set eyes and a prominent forehead. An abnormally small head (microcephaly), or sometimes an unusually large head (macrocephaly), may be present. Tags of skin in front of the ears (pre-auricular skin tags), one or more bent fingers (camptodactyly), and delayed growth have also been associated with some cases of agenesis of corpus callosum. In other cases wide-set eyes (telecanthus), a small nose with upturned (anteverted) nostrils, abnormally shaped ears, excessive neck skin, short hands, diminished muscle tone (hypotonia), abnormalities of the larynx, heart defects, and symptoms of Pierre-Robin syndrome may be present.

Aicardi syndrome, thought to be inherited as an X-linked dominant disorder, consists of agenesis of corpus callosum, infantile spasms, and abnormal eye structure. This disorder is an extremely rare congenital disorder in which frequent seizures, striking abnormalities of the eye’s middle coat (choroid) and retinal layers, and the absence of the structure linking the two cerebral hemispheres (the corpus callosum), accompany severe mental retardation. Only females are affected.

Andermann syndrome is a genetic disorder characterized by a combination of agenesis of corpus callosum, mental retardation, and progressive sensorimotor nervous system disturbances (neuropathy). All known cases of this disorder originate from Charlevois County and the Saguenay-Lac St. Jean area of Quebec, Canada. The gene causing this rare form of agenesis of the corpus callosum was recently identified and testing for this gene (SLC12A6) is currently available.

XLAG (X linked lissencephaly with ambiguous genitalia is a rare genetic disorder in which males have small and smooth brains (lissencephaly), small penis, severe mental retardation and intractable epilepsy. This is caused by mutations in the ARX gene. In females, these same mutations can cause agenesis of the corpus callosum alone, whereas less severe mutations in males can cause mental retardation. Testing for this disorder is also clinically available.

Agenesis of the corpus callosum behavior

This is an overview of the behavioral characteristics which are often evident in individuals with disorder of the corpus callosum. Behaviorally individuals with disorder of the corpus callosum may fall behind their peers in social and problem solving skills in elementary school or as they approach adolescence. In typical development, the fibers of the corpus callosum become more efficient as children approach adolescence. At that point children with an intact corpus callosum show rapid gains in abstract reasoning, problem solving, and social comprehension. Although a child with disorder of the corpus callosum may have kept up with his or her peers until this age, as the peer-group begins to make use of an increasingly efficient corpus callosum, the child with disorder of the corpus callosum falls behind in mental and social functioning. In this way, the behavioral challenges for individuals with disorder of the corpus callosum may become more evident as they grow into adolescence and young adulthood.

• Delays in attaining developmental milestones (for example, walking, talking, or reading). Delays may range from very subtle to highly significant.
• Clumsiness and poor motor coordination, particularly on skills that require coordination of left and right hands and feet (for example, swimming, bike riding, tying shoes, driving).
• Atypical sensitivity to particular sensory cues (for example, food textures, certain types of touch) but often with a high tolerance to pain.
• Difficulties on multidimensional tasks, such as using language in social situations (for example, jokes, metaphors), appropriate motor responses to visual information (for example, stepping on others’ toes, handwriting runs off the page), and the use of complex reasoning, creativity and problem solving (for example, coping with math and science requirements in middle school and high school, budgeting).
• Challenges with social interactions due to difficulty imagining potential consequences of behavior, being insensitive to the thoughts and feelings of others, and misunderstanding social cues (for example, being vulnerable to suggestion, gullible, and not recognizing emotions communicated by tone of voice).
• Mental and social processing problems become more apparent with age, with problems particularly evident from junior high school into adulthood.
• Limited insight into their own behavior, social problems, and mental challenges.

These symptoms occur in various combinations and severity. In many cases, they are attributed incorrectly to one or more of the following: personality traits, poor parenting, ADHD, autism spectrum disorders, Nonverbal Learning Disability, specific learning disabilities, or psychiatric disorders. It is critical to note that these alternative conditions are diagnosed through behavioral observation. In contrast, disorder of the corpus callosum is a definite structural abnormality of the brain diagnosed by an MRI. These alternative behavioral diagnoses may, in some cases, represent a reasonable description of the behavior of a person with disorder of the corpus callosum. However, they misrepresent the cause of the behavior.

Agenesis of the corpus callosum diagnosis

Ultrasound and magnetic resonance imaging (MRI) are imaging techniques that aid in diagnosis of agenesis of the corpus callosum.

Agenesis of the corpus callosum treatment

Agenesis of the corpus callosum treatmentis symptomatic and supportive. Anti-seizure medications, special education, physical therapy, and related services may be of benefit depending upon the range and severity of symptoms. When hydrocephalus is present it may be treated with a surgical shunt to drain the fluid from the brain cavity, thereby lowering the increased pressure on the brain. Genetic counseling may also be of benefit to families with this disorder.

Renal agenesis

Renal agenesis is the congenital absence or severe malformation of one (unilateral renal agenesis) or both kidneys (bilateral renal agenesis). The kidneys are part of the urinary system that also includes the bladder, the ureters, and the urethra. The kidneys filter out waste products from the blood and eliminate them as urine that flows through tubes called ureters to the bladder (the storage area) and then through the canal called the urethra.

Bilateral renal agenesis is the absence of both kidneys (sometimes called Potter’s Syndrome). Bilateral renal agenesis affects one to two out of every 10,000 births and is 2 l/2 times more frequent in males. Bilateral renal agenesis is associated with oligohydramnios, a deficiency of amniotic fluid in a pregnant woman. Because the amniotic fluid normally acts as a cushion, too little fluid can cause compression of the fetus resulting in further malformations and problems such as growth retardation; pulmonary hypoplasia (underdeveloped lungs); low-set ears; and a broad, flat nose.

Unilateral renal agenesis is the absence of one kidney. Unilateral renal agenesis is more common, occurring in one out of every 750-1,000 births. Unilateral renal agenesis is more common in males, and the left kidney is more frequently absent. The solitary kidney enlarges to compensate for the absent one and maintains normal kidney function. The ureter on the affected side may also be absent or abnormal. Abnormality of the reproductive tract on the affected side is sometimes associated with unilateral renal agenesis (more often in females than males).

Renal agenesis causes

Renal agenesis usually occurs sporadically. But 20-36% of the bilateral renal agenesis cases present a familial recurrence, occurring more commonly in infants with a parent who has a kidney malformation, especially unilateral renal agenesis. There is no known prevention for renal agenesis and genetic counseling
is recommended.

How do you know if your child has renal agenesis?

Some cases of bilateral renal agenesis are detected through prenatal ultrasound while other cases are not evident until birth. The ultrasound examination may reveal the absence of amniotic fluid, the absence of kidneys, and possibly the absence of the bladder. Babies with unilateral renal agenesis most often appear normal at birth. Unilateral renal agenesis is usually discovered incidentally through x-ray or ultrasound imaging of the abdomen for other reasons.

How can you help a child who has renal agenesis?

Because of the pulmonary hypoplasia associated with bilateral renal agenesis, kidney dialysis and kidney transplantation are usually not considered and no treatment is administered. With unilateral renal agenesis, the solitary kidney usually grows faster and becomes larger and heavier than normal. Therefore, the kidney becomes more susceptible to injury. Children with unilateral renal agenesis should avoid heavy contact sports. It is also important for them to have urine tests and blood pressure checks annually and kidney function checks every few years (or more frequently if the other tests are abnormal).

Treatment may become necessary for kidney problems such as obstruction or infection. Kidney transplantation may be necessary if the kidney becomes severely diseased, and dialysis or transplantation may be necessary to treat kidney failure. Patients receiving transplantation require anti-rejection medication and regular medical follow-up.

Renal agenesis life expectancy

Bilateral renal agenesis is fatal. Approximately 40% of the cases result in stillbirths. Infants rarely survive more than two days and usually die of respiratory failure within a few hours of birth. Children with unilateral renal agenesis usually have few or no problems in the first few years if the solitary kidney is healthy and there are no other anomalies. They do have a greater chance of developing high blood pressure and may experience a mild decrease in kidney function in later life. Sterility has been noted in some individuals with unilateral renal agenesis. Otherwise, these children usually live a normal life span.

Vaginal agenesis and uterine agenesis

Vaginal agenesis and uterine agensis also referred to as müllerian agenesis, müllerian aplasia or Mayer-Rokitansky-Küster-Hauser syndrome, is a rare malformation of the Mullerian duct with an incidence of 1 per 4,500–5,000 females ¹⁾. Müllerian agenesis is caused by embryologic underdevelopment of the müllerian duct, with resultant agenesis or atresia of the vagina, uterus, or both. Since lower vagina is usually normal and middle and upper 2/3 of vagina are absent, vaginal agenesis can also be thought as aplasia or dysplasia of the Mullerian duct ²⁾. Some researchers defended that absence of vagina is not a real syndrome but is a part of symptom complex. When uterine agensis (absence of the uterus) accompanies with vaginal agenesis, this is called as Mayer-Rokitansky-Küster-Hauser Syndrome ³⁾. Also, vaginal agenesis may be encountered as a part of androgen insensitivity syndrome (testicular feminization), Turner syndrome, Morris syndrome, or combined congenital defects ⁴⁾.

Diagnosis is often made at adolescence due to primary amenorrhea or coital problems with otherwise typical growth and pubertal development ⁵⁾. Abnormalities of sexual organs during this period may cause personality problems and poor body image. Also, inability to get pregnant during adulthood may cause low self-confidence ⁶⁾.

The most important steps in the effective management of müllerian agenesis are correct diagnosis of the underlying condition, evaluation for associated congenital anomalies, and psychosocial counseling in addition to treatment or intervention to address the functional effects of genital anomalies. The psychologic effect of the diagnosis of vaginal agenesis should not be underestimated. All patients with vaginal agenesis should be offered counseling and encouraged to connect with peer support groups. Future options for having children should be addressed with patients: options include adoption and gestational surrogacy. Assisted reproductive techniques with use of a gestational carrier (surrogate) have been shown to be successful for women with vaginal agenesis. There are several nonsurgical and surgical methods for treatment of vaginal agenesis. The purpose of the treatment is to create an adequate vaginal depth for penetration and to facilitate satisfactory sexual intercourse. Nonsurgical vaginal elongation by dilation should be the first-line approach. When well-counseled and emotionally prepared, almost all patients (90–96%) will be able to achieve anatomic and functional success by primary vaginal dilation. In cases in which surgical intervention is required, referrals to centers with expertise in this area should be considered because few surgeons have extensive experience in construction of the neovagina and surgery by a trained surgeon offers the best opportunity for a successful result. There are surgical methods, such as the Vecchietti techique, Davidoff technique, McIndoe technique (Abbe-McIndoe-Reed), and intestinal vaginoplasty ⁷⁾. The McIndoe (Abbe-McIndoe-Reed) technique is the most frequently mentioned procedure in literature ⁸⁾.

The American College of Obstetricians and Gynecologists makes the following recommendations and conclusions ⁹⁾:

• Patients with vaginal agenesis usually are identified when they are evaluated for primary amenorrhea with otherwise typical growth and pubertal development.
• Rudimentary müllerian structures are found in 90% of patients with vaginal agenesis by magnetic resonance imaging (MRI). On ultrasonography, these rudimentary müllerian structures are difficult to interpret and may be particularly misleading before puberty.
• Evaluation for associated congenital anomalies is essential because up to 53% of patients with vaginal agenesis have concomitant congenital malformations, especially of the urinary tract and skeleton.
• All patients with vaginal agenesis should be offered counseling and encouraged to connect with peer support groups.
• Future options for having children should be addressed with patients.
• Primary vaginal elongation by dilation is the appropriate first-line approach in most patients because it is safer, patient-controlled, and more cost effective than surgery.
• Because primary vaginal dilation is successful for more than 90–96% of patients, surgery should be reserved for the rare patient who is unsuccessful with primary dilator therapy or who prefers surgery after a thorough informed consent discussion with her gynecologic care provider and her respective parent(s) or guardian(s).
• Regardless of the surgical technique chosen, referrals to centers with expertise should be offered. The surgeon must be experienced with the procedure because the initial procedure is more likely to succeed than follow-up procedures.
• Although vulvar and vaginal intraepithelial neoplasia are possible, routine cytology testing is not regularly recommended because of the lack of a cervix.
• Sexually active women with vaginal agenesis should be aware that they are at risk of sexually transmitted infections (STIs) and, thus, condoms should be used for intercourse. Patients should be appropriately screened for sexually transmitted infections according to the guidelines for women without vaginal agenesis.
• Patients should be given a written medical summary of their condition, including a summary of concomitant malformations. This information may be useful if the patient requires urgent medical care or emergency surgery by a health care provider unfamiliar with vaginal agenesis.

Vaginal agenesis and uterine agenesis diagnosis

Initial evaluation of the patient without a uterus may include the following laboratory tests: testosterone level, FSH level, and karyotype. Initial radiologic evaluation includes transabdominal, translabial, or transrectal two-dimensional or three-dimensional ultra-sonography to assess for the presence of a midline uterus. Rudimentary müllerian structures are found in 90% of patients with müllerian agenesis by magnetic resonance imaging (MRI). Additionally, MRI can assess for the presence of endometrial activity within the müllerian structures ¹⁰⁾.

If active endometrium is present, the patient may experience cyclic or chronic abdominal pain. On ultrasonography, these rudimentary müllerian structures are difficult to interpret and may be particularly misleading before puberty ¹¹⁾. The MRI should be ordered with specific instructions to assess for müllerian remnants and the results should be interpreted by a radiologist with experience in evaluating müllerian tract structures ¹²⁾. The MRI typically can be done without contrast, but this decision can be left to the discretion of the radiologist.

Although laparoscopy is not necessary to diagnose müllerian agenesis, it may be useful in the evaluation and management of patients who report pelvic pain. Patients may experience pain from ovulation or endometriosis, which may improve with hormonal suppression. Patients also may develop endometriosis from retrograde menstruation from obstructed uterine horns. When obstructed uterine horns with the presence of active endometrium without an associated cervix and upper vagina are identified, then laparoscopic removal of the unilateral or bilateral obstructed uterine structures should be performed ¹³⁾. In most cases, surgical excision of the uterine horn results in improvement of the endometriosis ¹⁴⁾.

Evaluation for associated congenital anomalies is essential because up to 53% of patients with müllerian agenesis have concomitant congenital malformations, especially of the urinary tract and skeleton ¹⁵⁾. Multiple studies have confirmed the prevalence of renal anomalies in patients with müllerian agenesis to be 27–29%; therefore, ultrasound evaluation of the kidneys is warranted for all patients ¹⁶⁾. Skeletal anomalies (eg, scoliosis, vertebral arch disturbances, hypoplasia of the wrist) have been reported in approximately 8–32% of patients; therefore, spine radiography (X-ray) may reveal a skeletal anomaly even in asymptomatic patients ¹⁷⁾. There is an increased, but small, rate of hearing impairment in patients with müllerian agenesis ¹⁸⁾. A variety of uterine anomalies, including müllerian agenesis, can be seen with VATER/VACTERL association (vertebral anomalies, anorectal malformations, cardiovascular anomalies, tracheoesophageal fistula, esophageal atresia, renal anomalies, limb defects) ¹⁹⁾.

Karyotype evaluation of patients with müllerian agenesis will be 46,XX in most individuals. Given the heterogeneity of müllerian agenesis, it is not surprising that there have been several karyotype rearrangement abnormalities reported, including duplications and deletions, as well as individual gene mutations such as the WNT4 and WNT9 genes ²⁰⁾. A consultation with a geneticist with experience with müllerian agenesis may be helpful for additional genetic testing.

Vaginal agenesis and uterine agenesis treatment

Management of patients with müllerian agenesis includes psychosocial counseling as well as treatment of the anatomic anomalies. Options include vaginal elongation and the surgical creation of a neovagina.

Vaginal elongation

Primary vaginal elongation by dilation is the appropriate first-line approach in most patients because it is safer, patient controlled, and more cost effective than surgery ²¹⁾. When well-counseled and emotionally prepared, almost all patients (90–96%) will be able to achieve anatomic and functional success by primary vaginal dilation ²²⁾. Although it is a successful approach, many obstetrician–gynecologists do not receive training in primary vaginal dilation and may not feel equipped to counsel and coach their patients adequately ²³⁾. Additional training for the obstetrician–gynecologist or referral to a health care provider with experience guiding patients through primary dilation therapy (eg, an experienced pelvic floor physical therapist) may be warranted.

Assessing Patient Readiness

Nonsurgical or surgical vaginal elongation should wait until the patient is emotionally mature and expresses the desire to proceed with therapy. There are multiple risks of failure of dilation (eg, poor motivation, unstable relationships, interpersonal conflict, parental misunderstanding of diagnosis, sociocultural factors, and mental health issues), most of which are not anatomic and may predict poor adherence to postoperative dilation. Cognitive issues that affect adherence to dilation may include the following: limited comprehension of the diagnosis and anatomy, young age, underlying learning disability, and inadequate knowledge of the dilation process. Logistical barriers to successful dilation include lack of privacy and limited ability to travel to clinic for close follow-up. In a study of adolescent girls and women in whom müllerian agenesis was diagnosed, respondents reported lack of motivation, uncertainty that dilation would be successful, and the perception of dilation as a negative experience as barriers to use ²⁴⁾. Finally, anatomic considerations include discomfort and pain, scar from prior procedures, the absence of dimple, and the presence of multiple congenital anomalies ²⁵⁾. The patient should be encouraged to wait to start dilation until she feels emotionally and physically ready to begin the process.

Technique

Dilation should take place in a supportive setting with close monitoring that is tailored to the individual adolescent or woman. Initially, the patient should have a thorough examination with a mirror so that she can identify her clitoris, urethra, and distal vagina. She should be able to understand and demonstrate the appropriate location and angle to place the dilator. She should be instructed to place progressive dilators on the distal vaginal apex for 10–30 minutes one to three times per day ²⁶⁾. There are many dilator options available and the patient may want to try different dilators or vibrators to determine which ones are the most comfortable to use. Online support groups may provide links to purchase dilators online. Strategies for privacy should be discussed. Ideally patients may be seen weekly or biweekly for close follow-up to monitor progress, to manage adverse effects (including pain and bleeding), and to provide encouragement. Involvement of an experienced pelvic floor physical therapist also may be beneficial ²⁷⁾. Notably, there is no set length that must be achieved before penetrative intercourse is permitted; indeed, elongation by vaginal intercourse alone can be successful ²⁸⁾.

Troubleshooting

Common adverse effects reported with dilation include urinary symptoms, bleeding, and pain. If these are experienced, the patient should be evaluated if possible to assess for vaginal abrasion, urinary dysfunction, and urinary tract infection ²⁹⁾. The most commonly recommended treatments for bleeding are to increase use of lubricant, switch to a wider or softer dilator, and rest the pelvis until the bleeding has ceased. Treatments for pain include switching to a wider or softer dilator and increasing use of lubricants. The patient also should be assessed for dysfunctional voiding and vaginismus.

Defining Success and Failure

Patients who have previously attempted primary dilation may have been told or may assume that they “failed” dilation; however, close questioning often reveals that the patients may have not had an adequate understanding of the process and may not have been appropriately coached ³⁰⁾. A dilated vagina may not appear on examination as a typical vagina; however, appearance does not dictate function. Although some studies define success anatomically by a length of 6 cm or longer ³¹⁾, the best definition of success is a vagina that is functional for comfortable sexual activity, as reported by the patient. There is no starting length associated with functional success, and, therefore, even patients with a flush vaginal dimple should be encouraged to dilate as first-line therapy. Based on expert opinion, patients who successfully use dilation therapy may require continuation of dilation on an intermittent basis if they are not regularly engaging in vaginal intercourse ³²⁾. Patients who have stopped dilating should be reassured that they will not cause themselves harm, but they may need to resume dilation before sexual activity in the future. The patient should be empowered to determine when she is ready to start dilation and encouraged to proceed with dilation at her own rate.

Surgical creation of a neovagina

Surgical creation of a vagina requires ongoing postoperative dilation or vaginal intercourse to maintain adequate vaginal length and diameter; therefore, it is not a method to avoid vaginal dilator therapy. Because primary vaginal dilation is successful for more than 90–96% of patients, surgery should be reserved for the rare patient who is unsuccessful with primary dilator therapy ³³⁾ or who prefers surgery after a thorough informed consent discussion with her gynecologic care provider and her respective parent(s) or guardian(s). Unlike primary vaginal dilation therapy, failing to adhere to postsurgery dilation can have deleterious effects.

The primary aim of surgery is the creation of a vaginal canal to allow penetrative intercourse. The timing of the surgery depends on the patient and the type of procedure planned. Surgical procedures often are performed in late adolescence or young adulthood when the patient is mature enough to agree to the procedure and to be able to adhere to postoperative dilation.

Several surgical techniques may be used to create a neovagina. Regardless of the surgical technique chosen, referrals to centers with expertise should be offered. The surgeon must be experienced with the procedure because the initial procedure is more likely to succeed than follow-up procedures. Patients should be thoroughly counseled about surgical pain and the need for very close postoperative care. Compared with primary vaginal dilation, vaginoplasty complications are much more common and include bladder or rectal perforation, graft necrosis, hair-bearing vaginal skin, fistulae, diversion colitis, inflammatory bowel disease, and adenocarcinoma ³⁴⁾. At present, there is no consensus in the literature regarding the best option for surgical technique to afford the best functional outcome and sexual satisfaction ³⁵⁾.

Historically, the most common surgical procedure used to create a neovagina has been the modified Abbe–McIndoe operation. This procedure involves the dissection of a space between the rectum and bladder, placement of a stent covered with a split-thickness skin graft into the space, and the diligent use of vaginal dilation postoperatively. Other procedures for the creation of the neovagina are the Vecchietti procedure and other laparoscopic modifications of operations previously performed by laparotomy ³⁶⁾. The laparoscopic Vecchietti procedure is a modification of the open technique in which a neovagina is created using an external traction device that is affixed temporarily to the abdominal wall ³⁷⁾. Another procedure, the Davydov procedure, was developed as a three-stage operation that requires dissection of the rectovesicular space with abdominal mobilization of a segment of the peritoneum and subsequent attachment of the peritoneum to the introitus ³⁸⁾. Other vaginoplasty graft options include bowel, buccal mucosa, amnion, and various other allografts. Postoperative dilation is essential to prevent significant neovaginal stenosis and contracture; therefore, these techniques are not recommended if the patient objects to dilation. Dilators must intermittently be used until the patient engages in regular and frequent sexual intercourse.