The diagnosis is often one of exclusion found during the workup of delayed puberty.

A paper published in 2012 by Prof. Jacques Young highlights a typical example of the diagnostic work up involved in a suspected case of KS/CHH.

One of the biggest problems in the diagnosis of KS and other forms of CHH is the ability to distinguish between a normal constitutional delay of puberty and KS or CHH.

The main biochemical parameters in men are low serum testosterone and low levels of the gonadotropins LH and FSH, and in women low serum oestrogen and low levels of LH and FSH.

For both males and females with constitutional delay of puberty, endogenous puberty will eventually commence without treatment. However a delay in treatment in a case of KS/HH will delay the physical development of the patient and can cause severe psychological damage. The "wait and see" approach applied to "late bloomers" is probably counterproductive to the needs of the patient whereas a step-by-step approach with hormone replacement therapy used with slowly increasing doses can be used as a diagnostic tool.

Post natal diagnosis of KS / CHH before the age of 6 months is sometimes possible. The normal post natal hormonal surge of gonadotropins along with testosterone or oestrogen is absent in babies with KS / CHH. This lack of detectable hormones in the blood can be used as a diagnostic indicator, especially in male infants.

Normally testicular enlargement is the key sign for the onset of puberty in boys however the use of nighttime LH sampling can help predict the onset of puberty.

In females diagnosis is sometimes further delayed as other causes of amenorrhoea normally have to be investigated first before a case of KS/CHH is considered. KS/CHH can still occur in females in cases when menstruation has begun but stopped after one or two menstrual bleeds. A study of GnRH deficient women in 2011 showed that 10% had experienced one or two bleeds before the onset of amenorrhoea.

In males, treatment with age-appropriate levels of testosterone can be used to distinguish between a case of KS/CHH from a case of delayed puberty. If just delayed the testosterone can "kick-start" endogenous puberty, as demonstrated by testicular enlargement, whereas in the case of KS/CHH there will be no testicular enlargement while on testosterone therapy alone. If no puberty is apparent, especially no testicular development, then a review by a reproductive endocrinologist may be appropriate. Dr Richard Quinton, a leading UK expert on KS/CHH, suggests that if puberty is not apparent by the age of 16 then the patient should be referred for endocrinological review.

A full endocrine workup will be required to measure the levels of the other pituitary hormones, especially prolactin, to check that the pituitary gland is working correctly. There can be other general health issues such as being overweight or having an underlying chronic or acute illness which could cause a delay of puberty. This makes it essential for a patient to get a full endocrine review to distinguish between a case of KS/CHH and another cause for the pubertal delay.

Bone age can be assessed using hand and wrist X-rays. If the bone age is significantly lower than the chronological age of the patient, this could suggest delayed puberty unless there is another underlying reason for the discrepancy.

A karyotype may be performed to rule out Klinefelter syndrome and Turner syndrome, although the hormones levels would also rule out both these relatively common reasons for hypogonadism.

A magnetic resonance imaging (MRI) scan can be used to determine whether the olfactory bulb is present and to check for any physical irregularities of the pituitary gland or hypothalamus.

A standard smell test can be used to check for anosmia, but it must be remembered that even in total anosmia various substances (such as menthol and alcohol) can still be detected by direct stimulation of the trigeminal nerve.

Genetic screening can be carried out, but in light of the unknown genes involved in the majority of KS and CHH cases, a negative result will not rule out a possible diagnosis.

A review paper published in 2014 highlighted the need for doctors to be aware of the possible diagnosis of KS / HH if pubertal delay is found alongside associated "red flag" symptoms. The symptoms listed in the paper were split into two categories; reproductive symptoms associated with the lack of mini puberty seen between birth and six months of age and non-reproductive symptoms which are associated with specific forms of HH. As with other review papers the authors also warned against the "wait and see" approach when puberty appears to be delayed.

Low testosterone can be identified through a simple blood test performed by a laboratory, ordered by a health care provider. Blood for the test must be taken in the morning hours, when levels are highest, as levels can drop by as much as 13% during the day and all normal reference ranges are based on morning levels. However, low testosterone in the absence of any symptoms does not clearly need to be treated.

Normal total testosterone levels depend on the man's age but generally range from 240–950 ng/dL (nanograms per deciliter) or 8.3-32.9 nmol/L (nanomoles per liter). Some men with normal total testosterone have low free or bioavailable testosterone levels which could still account for their symptoms. Men with low serum testosterone levels should have other hormones checked, particularly luteinizing hormone to help determine why their testosterone levels are low and help choose the most appropriate treatment (most notably, testosterone is usually not appropriate for secondary or tertiary forms of male hypogonadism, in which the LH levels are usually reduced).

Treatment is often prescribed for total testosterone levels below 230 ng/dL with symptoms. If the serum total testosterone level is between 230 and 350 ng/dL, free or bioavailable testosterone should be checked as they are frequently low when the total is marginal.

The standard range given is based off widely varying ages and, given that testosterone levels naturally decrease as humans age, age-group specific averages should be taken into consideration when discussing treatment between doctor and patient. In men, testosterone falls approximately 1 to 3 percent each year.

- Blood testing

A position statement by the Endocrine Society expressed dissatisfaction with most assays for total, free, and bioavailable testosterone. In particular, research has questioned the validity of commonly administered assays of free testosterone by radioimmunoassay. The free androgen index, essentially a calculation based on total testosterone and sex hormone-binding globulin levels, has been found to be the worst predictor of free testosterone levels and should not be used. Measurement by equilibrium dialysis or mass spectroscopy is generally required for accurately results, particularly for free testosterone which is present normal in such small concentrations.

The consequences to the girl with XX gonadal dysgenesis:

1. Her gonads cannot make estrogen, so her breasts will not develop and her uterus will not grow and menstruate until she is given estrogen. This is often given through the skin now.

2. Her gonads cannot make progesterone, so her menstrual periods will not be predictable until she is given a progestin, still usually as a pill.

3. Her gonads cannot produce eggs so she will not be able to conceive children naturally. A woman with a uterus but no ovaries may be able to become pregnant by implantation of another woman's fertilized egg (embryo transfer).

Reversal of symptoms have been reported in between 15% to 22% of cases. The causes of this reversal are still under investigation but have been reported in both males and females.

Reversal appears to be associated with 14 of the known gene defects linked to KS/CHH. The study suggests no obvious gene defect showing a tendency to allow reversal. There is a suggestion that the TAC3 and TACR3 mutations might allow for a slightly higher chance of reversal, but the numbers involved are too low to confirm this. The ANOS1 mutations appear to be least likely to allow reversal with to date only one recorded instance in medical literature. Even male patients who previous had micro-phallus or cryptorchidism have been shown to undergo reversal of symptoms.

The reversal might not be permanent and remission can occur at any stage; the paper suggests that this could be linked to stress levels. The paper highlighted a reversal case that went into remission but subsequently achieved reversal again, strongly suggesting an environmental link.

Reversal cases have been seen in cases of both KS and normosmic CHH but appear to be less common in cases of KS (where the sense of smell is also affected). A paper published in 2016 agreed with the theory that there is a strong environmental or epigenetic link to the reversal cases. The precise mechanism of reversal is unclear and is an area of active research.

Reversal would be apparent if testicular development was seen in men while on testosterone therapy alone or in women who menstruate or achieved pregnancy while on no treatment. To date there have been no recorded cases of the reversal of anosmia found in Kallmann syndrome cases.

Testing serum LH and FSH levels are often used to assess hypogonadism in women, particularly when menopause is believed to be happening. These levels change during a woman's normal menstrual cycle, so the history of having ceased menstruation coupled with high levels aids the diagnosis of being menopausal. Commonly, the post-menopausal woman is not called hypogonadal if she is of typical menopausal age. Contrast with a young woman or teen, who would have hypogonadism rather than menopause. This is because hypogonadism is an abnormality, whereas menopause is a normal change in hormone levels. In any case, the LH and FSH levels will rise in cases of primary hypogonadism or menopause, while they will be low in women with secondary or tertiary hypogonadism.

Hypogonadism is often discovered during evaluation of delayed puberty, but ordinary delay, which eventually results in normal pubertal development, wherein reproductive function is termed constitutional delay. It may be discovered during an infertility evaluation in either men or women.

Common hormonal test include determination of FSH and testosterone levels. A blood sample can reveal genetic causes of infertility, e.g. Klinefelter syndrome, a Y chromosome microdeletion, or cystic fibrosis.

Some strategies suggested or proposed for avoiding male infertility include the following:

- Avoiding smoking as it damages sperm DNA

- Avoiding heavy marijuana and alcohol use.

- Avoiding excessive heat to the testes.

- Maintaining optimal frequency of coital activity: sperm counts can be depressed by daily coital activity and sperm motility may be depressed by coital activity that takes place too infrequently (abstinence 10–14 days or more).

- Wearing a protective cup and jockstrap to protect the testicles, in any sport such as baseball, football, cricket, lacrosse, hockey, softball, paintball, rodeo, motorcross, wrestling, soccer, karate or other martial arts or any sport where a ball, foot, arm, knee or bat can come into contact with the groin.

- Diet: Healthy diets (i.e. the Mediterranean diet) rich in such nutrients as omega-3 fatty acids, some antioxidants and vitamins, and low in saturated fatty acids (SFAs) and trans-fatty acids (TFAs) are inversely associated with low semen quality parameters. In terms of food groups, fish, shellfish and seafood, poultry, cereals, vegetables and fruits, and low-fat dairy products have been positively related to sperm quality. However, diets rich in processed meat, soy foods, potatoes, full-fat dairy products, coffee, alcohol and sugar-sweetened beverages and sweets have been inversely associated with the quality of semen in some studies. The few studies relating male nutrient or food intake and fecundability also suggest that diets rich in red meat, processed meat, tea and caffeine are associated with a lower rate of fecundability. This association is only controversial in the case of alcohol. The potential biological mechanisms linking diet with sperm function and fertility are largely unknown and require further study.

Because of the inability of the streak gonads to produce sex hormones (both estrogens and androgens), most of the secondary sex characteristics do not develop. This is especially true of estrogenic changes such as breast development, widening of the pelvis and hips, and menstrual periods. Because the adrenal glands can make limited amounts of androgens and are not affected by this syndrome, most of these girls will develop pubic hair, though it often remains sparse.

Evaluation of delayed puberty usually reveals the presence of pubic hair, but elevation of gonadotropins, indicating that the pituitary is providing the signal for puberty but the gonads are failing to respond. The next steps of the evaluation usually include checking a karyotype and imaging of the pelvis. The karyotype reveals XX chromosomes and the imaging demonstrates the presence of a uterus but no ovaries (the streak gonads are not usually seen by most imaging). At this point it is usually possible for a physician to make a diagnosis of XX gonadal dysgenesis.

IHH is divided into two syndromes: IHH with olfactory alterations or anosmia, Kallmann syndrome and IHH with normal smell (normosmic IHH).

Kallmann syndrome is responsible for approximately 50% of all cases of the condition. It is associated with mutations in "KAL1", "FGFR1/FGF8", "FGF17", "IL17RD", "PROKR2", "NELF", "CHD7"(which positively regulates GnRH secretion), HS6ST1, "FLRT3", "SPRY4", DUSP6, "SEMA3A", and "WDR11 (gene)", genes which are related to defects in neuronal migration.

Gene defects associated with IHH and normal smell include "PROKR2, FGFR1, FGF8, CHD7, DUSP6," and "WDR11", as in KS, but in addition

also mutations in "KISS1R", "TACR3", GNRH1/GNRHR, LEP/LEPR, HESX1, FSHB, and LHB.

GnRH insensitivity is the second most common cause of IHH, responsible for up to 20% of cases.

A minority of less than 5-10% is due to inactivating mutations in genes which positively regulate GnRH secretion such as ,"CHD7", "KISS1R", and "TACR3".

The causes of about 25% of all IHH cases are still unknown.

Isolated hypogonadotropic hypogonadism (IHH), also called idiopathic or congenital hypogonadotropic hypogonadism (CHH), as well as isolated or congenital gonadotropin-releasing hormone deficiency (IGD) constitutes a small subset of cases of hypogonadotropic hypogonadism (HH).

IHH is due to deficiency in or insensitivity to gonadotropin-releasing hormone (GnRH), where the function and anatomy of the anterior pituitary is otherwise normal, and secondary causes of HH are not present.

Treatment of HH may consist of administration of either a GnRH agonist or a gonadotropin formulation in the case of primary HH and treatment of the root cause (e.g., a tumor) of the symptoms in the case of secondary HH. Alternatively, hormone replacement therapy with androgens and estrogens in males and females, respectively, may be employed.

Androgen deficiency is not usually checked for diagnosis in healthy women.

The diagnosis of Wilson–Turner syndrome is based upon a clinical evaluation, a detailed patient history, and identification of characteristic features. Molecular genetic testing for mutations in the HDAC8 gene is now available to confirm the diagnosis.

Audiometry (measuring ability to hear sounds of a particular pitch) is usually abnormal, but the findings are not particularly specific and an audiogram is not sufficient to diagnose Pendred syndrome. A thyroid goitre may be present in the first decade and is usual towards the end of the second decade. MRI scanning of the inner ear usually shows widened or large vestibular aqueducts with enlarged endolymphatic sacs and may show abnormalities of the cochleae that is known as Mondini dysplasia. Genetic testing to identify the pendrin gene usually establishes the diagnosis. If the condition is suspected, a "perchlorate discharge test" is sometimes performed. This test is highly sensitive, but may also be abnormal in other thyroid conditions. If a goitre is present, thyroid function tests are performed to identify mild cases of thyroid dysfunction even if they are not yet causing symptoms.

Treatment may consist of hormone replacement therapy with androgens in either sex. Alternatively, gonadotropin-releasing hormone (GnRH)/GnRH agonists or gonadotropins may be given (in the case of "hypogonadotropic" hypoandrogenism). The Food and Drug Administration (FDA) stated in 2015 that neither the benefits nor the safety of testosterone have been established for low testosterone levels due to aging. The FDA has required that testosterone pharmaceutical labels include warning information about the possibility of an increased risk of heart attacks and stroke.

Isolated hypogonadotropic hypogonadism (IHH), also called idiopathic or congenital hypogonadotropic hypogonadism (CHH), as well as isolated or congenital gonadotropin-releasing hormone deficiency (IGD), is a condition which results in a small subset of cases of hypogonadotropic hypogonadism (HH) due to deficiency in or insensitivity to gonadotropin-releasing hormone (GnRH) where the function and anatomy of the anterior pituitary is otherwise normal and secondary causes of HH are not present.

The Wilson–Turner syndrome is characterized by mild to moderate range of intellectual disability, obesity, tapered fingers, and mood swings. Males also suffer from gynecomastia and hypogonadism. In order to be diagnosed with Wilson-Turner Syndrome, male patients must suffer from intellectual disability, obesity, and gynecomastia. Females do not necessarily have to have noticeable phenotype but can be diagnosed with this disorder by studying her family history and identifying others with the disorder. It has been noted that children with Wilson-Turner Syndrome will display speech development delay and excessive drooling. Males can be confirmed by testing androgen levels. Female carriers will show silencing of the gene a complex X inactivation.

Hypogonadotropic hypogonadism (HH), also known as secondary or central hypogonadism, as well as gonadotropin-releasing hormone deficiency or gonadotropin deficiency (GD), is a medical condition characterized by hypogonadism due to an impaired secretion of gonadotropins, including follicle-stimulating hormone (FSH) and luteinizing hormone (LH), by the pituitary gland in the brain, and in turn decreased gonadotropin levels and a resultant lack of sex steroid production.

The fertile eunuch syndrome is a cause of hypogonadotropic hypogonadism caused by a luteinizing hormone deficiency. It is characterized by hypogonadism with spermatogenesis. Pasqualini and Bur published the first case of eunuchoidism with preserved spermatogenesis in 1950 in la Revista de la Asociación Médica Argentina.

The hypoandrogenism with spermatogenesis syndrome included: (a) eunuchoidism, (b) testis with normal spermatogenesis and full volume, with mature spermatozoids in a high proportion of seminiferous tubes and undifferentiated and immature Leydig cells (c) full functional compensation through the administration of chorionic gonadotropin hormone, while hCG is administered (d) total urinary gonadotrophins within normal limits (e) this definition implies the normal activity of the pituitary and the absence of congenital malformations in general. In describing five other similar cases in 1953, Mc Cullagh & al coined the term fertile eunuch introducing it in the English literature. Unfortunately, this term is incorrect and should not be employed. Indeed, these patients are not really eunuchs. Moreover, as it will be explained later, they are not usually fertile if not treated.

A first step in the understanding of the physiopathology of Pasqualini syndrome was the absence of Lutheinizing Hormone (LH) in plasma and urine of patients. The second breakthrough was the functional and genetic studies that validated the hypothesis of a functional deficit of LH in these men. Inactivating LH mutations will then also be described in some women. Different groups demonstrated in these cases a LH with varying degrees of immunological activity but biologically inactive in most of the patients, due to one or more inactivating mutations in the LHB gene. Finally, the full comprehension of Pasqualini syndrome allowed to reverse the hypoandrogenic phenotype and to restore fertility in these patients through the use of chorionic gonadotropin and the modern in-vitro fertility techniques

Gonadotropin-releasing hormone (GnRH) insensitivity is a rare autosomal recessive genetic and endocrine syndrome which is characterized by inactivating mutations of the gonadotropin-releasing hormone receptor (GnRHR) and thus an insensitivity of the receptor to gonadotropin-releasing hormone (GnRH), resulting in a partial or complete loss of the ability of the gonads to synthesize the sex hormones. The condition manifests itself as isolated hypogonadotropic hypogonadism (IHH), presenting with symptoms such as delayed, reduced, or absent puberty, low or complete lack of libido, and infertility, and is the predominant cause of IHH when it does not present alongside anosmia.

Diagnosis is based on clinical findings.

'Clinical findings'

- Profound congenital sensorineural deafness is present

- CT scan or MRI of the inner ear shows no recognizable structure in the inner ear.

- As michel's aplasia is associated with LAMM syndrome there will be Microtia and microdontia present(small sized teeth).

Molecular genetic Testing

1. "FGF3" is the only gene, whose mutation can cause congenital deafness with Michel's aplasia, microdontia and microtia

Carrier testing for at-risk relatives requires identification of mutations which are responsible for occurrence of disease in the family.

No specific treatment exists for Pendred syndrome. Speech and language support and hearing aids are important. Cochlear implants may be needed if the hearing loss drops to severe to profound levels and can improve language skills. If thyroid hormone levels are decreased, thyroid hormone supplements may be required. Patients are advised to take precautions against head injury.

Even though clinical diagnostic criteria have not been 100 percent defined for genitopatellar syndrome, the researchers stated that the certain physical features could relate to KAT6B mutation and result in the molecular genetic testing. The researchers stated that the Individuals with two major features or one major feature and two minor features are likely to have a KAT6B mutation.

To diagnose the Genitopatellar Syndrome, there are multiple ways to evaluate.

Medical genetics consultation

- Evaluation by developmental specialist

- Feeding evaluation

- Baseline hearing evaluation

- Thyroid function tests

- Evaluation of males for cryptorchidism

- Orthopedic evaluation if contractures are present or feet/ankles are malpositioned

- Hip radiographs to evaluate for femoral head dislocation

- Renal ultrasound examination for hydronephrosis and cysts

- Echocardiogram for congenital heart defects

- Evaluation for laryngomalacia if respiratory issues are present

- Evaluation by gastroenterologist as needed, particularly if bowel malrotation is suspected

One of the main characteristics of this disorder is adrenal insufficiency, which is a reduction in adrenal gland function resulting from incomplete development of the gland's outer layer (the adrenal cortex). Adrenal insufficiency typically begins in infancy or in childhood and can cause vomiting, difficulty with feeding, dehydration, extremely low blood sugar (hypoglycemia), low sodium levels, and shock. However, adult-onset cases have also been described. See also Addison's Disease.

Affected males may also lack male sex hormones, which leads to underdeveloped reproductive tissues, undescended testicles (cryptorchidism), delayed puberty, and an inability to father children (infertility). These characteristics are known as hypogonadotropic hypogonadism. Females are rarely affected by this disorder, but a few cases have been reported of adrenal insufficiency or a lack of female sex hormones, resulting in underdeveloped reproductive tissues, delayed puberty, and an absence of menstruation.

Diagnosis of 48, XXXY is usually done by a standard karyotype. A karyotype is a chromosomal analysis in which a full set of chromosomes can be seen for an individual. The presence of the additional 2 X chromosomes on the karyotype are indicative of XXXY syndrome.

Another way to diagnosis 48, XXXY is by chromosomal microarray showing the presence of extra X chromosomes. Chromosomal microarray (CMA) is used to detect extra or missing chromosomal segments or whole chromosomes. CMA uses microchip-based testing to analyze many pieces of DNA. Males with 48, XXXY are diagnosed anywhere from before birth to adulthood as a result of the range in the severity of symptoms. The age range at diagnosis is likely due to the fact that XXXY is a rare syndrome, and does not cause as extreme phenotypes as other variants of Klinefelter syndrome (such as XXXXY).

Diagnostic testing could also be done via blood samples. Elevated levels of follicle stimulating hormone, luteinizing hormone, and low levels of testosterone can be indicative of this syndrome.

Prevention for Alström Syndrome is considered to be harder compared to other diseases/syndromes because it is an inherited condition. However, there are other options that are available for parents with a family history of Alström Syndrome. Genetic testing and counseling are available where individuals are able to meet with a genetic counselor to discuss risks of having the children with the disease. The genetic counselor may also help determine whether individuals carry the defective ALSM1 gene before the individuals conceive a child. Some of the tests the genetic counselors perform include chorionic villus sampling (CVS), Preimplantation genetic diagnosis (PGD), and amniocentesis. With PGD, the embryos are tested for the ALSM1 gene and only the embryos that are not affected may be chosen for implantation via in vitro fertilization.