The diagnosis of AOS is a clinical diagnosis based on the specific features described above. A system of major and minor criteria was proposed.

The combination of two major criteria would be sufficient for the diagnosis of AOS, while a combination of one major and one minor feature would be suggestive of AOS. Genetic testing can be performed to test for the presence of mutation in one of the known genes, but these so far only account for an estimated 50% of patients with AOS. A definitive diagnosis may therefore not be achieved in all cases.

If the medical history and the actual exam of the hemangioma look typical for PHACE Syndrome, more tests are ordered to confirm the diagnosis. These tests may include:

- Ultrasound

- Magnetic resonance imaging (MRI)

- Magnetic resonance angiography of the brain (MRA)

- Echocardiogram

- Eye exam by an eye doctor

- Other tests may be needed for diagnosis and treatment

Ultrasound remains as one of the only effective ways of prenatally diagnosing Larsen syndrome. Prenatal diagnosis is extremely important, as it can help families prepare for the arrival of an infant with several defects. Ultrasound can capture prenatal images of multiple joint dislocations, abnormal positioning of legs and knees, depressed nasal bridge, prominent forehead, and club feet. These symptoms are all associated with Larsen syndrome, so they can be used to confirm that a fetus has the disorder.

The overall prognosis is excellent in most cases. Most children with Adams–Oliver syndrome can likely expect to have a normal life span. However, individuals with more severe scalp and cranial defects may experience complications such as hemorrhage and meningitis, leading to long-term disability.

Patients with abnormal cardiac and kidney function may be more at risk for hemolytic uremic syndrome

Prognoses for 3C syndrome vary widely based on the specific constellation of symptoms seen in an individual. Typically, the gravity of the prognosis correlates with the severity of the cardiac abnormalities. For children with less severe cardiac abnormalities, the developmental prognosis depends on the cerebellar abnormalities that are present. Severe cerebellar hypoplasia is associated with growth and speech delays, as well as hypotonia and general growth deficiencies.

Hydrolethalus can be readily diagnosed during pregnancy through the use of ultrasound, which will often reveal hydrocephaly and an abnormal structure of the brain.

While Larsen syndrome can be lethal if untreated, the prognosis is relatively good if individuals are treated with orthopedic surgery, physical therapy, and other procedures used to treat the symptoms linked with Larsen syndrome.

The outcome of this disease is dependent on the severity of the cardiac defects. Approximately 1 in 3 children with this diagnosis require shunting for the hydrocephaly that is often a consequence. Some children require extra assistance or therapy for delayed psychomotor and speech development, including hypotonia.

No cure or treatment option for individuals with Hydrolethalus syndrome currently exist.

Usually the hemangioma requires medical therapy. The child may need other therapies, depending on what other organs or structures are involved.

When vWD is suspected, blood plasma of a patient must be investigated for quantitative and qualitative deficiencies of vWF. This is achieved by measuring the amount of vWF in a vWF antigen assay and the functionality of vWF with a glycoprotein (GP)Ib binding assay, a collagen binding assay, or a ristocetin cofactor activity (RiCof) or ristocetin induced platelet agglutination (RIPA) assays. Factor VIII levels are also performed because factor VIII is bound to vWF which protects the factor VIII from rapid breakdown within the blood. Deficiency of vWF can then lead to a reduction in factor VIII levels, which explains the elevation in PTT. Normal levels do not exclude all forms of vWD, particularly type 2, which may only be revealed by investigating platelet interaction with subendothelium under flow, a highly specialized coagulation study not routinely performed in most medical laboratories. A platelet aggregation assay will show an abnormal response to ristocetin with normal responses to the other agonists used. A platelet function assay may give an abnormal collagen/epinephrine closure time, and in most cases, a normal collagen/ADP time. Type 2N may be considered if factor VIII levels are disproportionately low, but confirmation requires a "factor VIII binding" assay. Additional laboratory tests that help classify sub-types of vWD include von-willebrand multimer analysis, modified ristocetin induced platelet aggregation assay and vWF propeptide to vWF antigen ratio propeptide. In cases of suspected acquired von-Willebrand syndrome, a mixing study study (analysis of patient plasma along with pooled normal plasma/PNP and a mixture of the two tested immediately, at one hour, and at two hours) should be performed. Detection of vWD is complicated by vWF being an acute phase reactant with levels rising in infection, pregnancy, and stress.

Other tests performed in any patient with bleeding problems are a complete blood count-CBC (especially platelet counts), activated partial thromboplastin time-APTT, prothrombin time with International Normalized Ratio-PTINR, thrombin time-TT, and fibrinogen level. Testing for factor IX may also be performed if hemophilia B is suspected. Other coagulation factor assays may be performed depending on the results of a coagulation screen. Patients with von Willebrand disease typically display a normal prothrombin time and a variable prolongation of partial thromboplastin time.

The testing for vWD can be influenced by laboratory procedures. Numerous variables exist in the testing procedure that may affect the validity of the test results and may result in a missed or erroneous diagnosis. The chance of procedural errors are typically greatest during the preanalytical phase (during collecting storage and transportation of the specimen) especially when the testing is contracted to an outside facility and the specimen is frozen and transported long distances. Diagnostic errors are not uncommon, and the rate of testing proficiency varies amongst laboratories, with error rates ranging from 7 to 22% in some studies to as high as 60% in cases of misclassification of vWD subtype. To increase the probability of a proper diagnosis, testing should be done at a facility with immediate on-site processing in a specialized coagulation laboratory.

Diagnosis of 22q11.2 deletion syndrome can be difficult due to the number of potential symptoms and the variation in phenotypes between individuals. It is suspected in patients with one or more signs of the deletion. In these cases a diagnosis of 22q11.2DS is confirmed by observation of a deletion of part of the long arm (q) of chromosome 22, region 1, band 1, sub-band 2. Genetic analysis is normally performed using fluorescence "in situ" hybridization (FISH), which is able to detect microdeletions that standard karyotyping (e.g. G-banding) miss. Newer methods of analysis include Multiplex ligation-dependent probe amplification assay (MLPA) and quantitative polymerase chain reaction (qPCR), both of which can detect atypical deletions in 22q11.2 that are not detected by FISH. qPCR analysis is also quicker than FISH, which can have a turn around of 3 to 14 days.

A 2008 study of a new high-definition MLPA probe developed to detect copy number variation at 37 points on chromosome 22q found it to be as reliable as FISH in detecting normal 22q11.2 deletions. It was also able to detect smaller atypical deletions that are easily missed using FISH. These factors, along with the lower expense and easier testing mean that this MLPA probe could replace FISH in clinical testing.

Genetic testing using BACs-on-Beads has been successful in detecting deletions consistent with 22q11.2DS during prenatal testing. Array-comparative genomic hybridization (array-CGH) uses a large number of probes embossed in a chip to screen the entire genome for deletions or duplications. It can be used in post and pre-natal diagnosis of 22q11.2.

Fewer than 5% of individuals with clinical symptoms of the 22q11.2 deletion syndrome have normal routine cytogenetic studies and negative FISH testing. In these cases, atypical deletions are the cause. Some cases of 22q11.2 deletion syndrome have defects in other chromosomes, notably a deletion in chromosome region 10p14.

Dozens of congenital metabolic diseases are now detectable by newborn screening tests, especially the expanded testing using mass spectrometry. This is an increasingly common way for the diagnosis to be made and sometimes results in earlier treatment and a better outcome. There is a revolutionary Gas chromatography–mass spectrometry-based technology with an integrated analytics system, which has now made it possible to test a newborn for over 100 mm genetic metabolic disorders.

Because of the multiplicity of conditions, many different diagnostic tests are used for screening. An abnormal result is often followed by a subsequent "definitive test" to confirm the suspected diagnosis.

Common screening tests used in the last sixty years:

- Ferric chloride test (turned colors in reaction to various abnormal metabolites in urine)

- Ninhydrin paper chromatography (detected abnormal amino acid patterns)

- Guthrie bacterial inhibition assay (detected a few amino acids in excessive amounts in blood) The dried blood spot can be used for multianalyte testing using Tandem Mass Spectrometry (MS/MS). This given an indication for a disorder. The same has to be further confirmed by enzyme assays, IEX-Ninhydrin, GC/MS or DNA Testing.

- Quantitative measurement of amino acids in plasma and urine

- IEX-Ninhydrin post column derivitization liquid ion-exchange chromatography (detected abnormal amino acid patterns and quantitative analysis)

- Urine organic acid analysis by gas chromatography–mass spectrometry

- Plasma acylcarnitines analysis by mass spectrometry

- Urine purines and pyrimidines analysis by gas chromatography-mass spectrometry

Specific diagnostic tests (or focused screening for a small set of disorders):

- Tissue biopsy or necropsy: liver, muscle, brain, bone marrow

- Skin biopsy and fibroblast cultivation for specific enzyme testing

- Specific DNA testing

A 2015 review reported that even with all these diagnostic tests, there are cases when "biochemical testing, gene sequencing, and enzymatic testing can neither confirm nor rule out an IEM, resulting in the need to rely on the patient's clinical course."

Tests for neural tube defects include ultrasound examination and measurement of maternal serum alpha-fetoprotein (MSAFP). Second trimester ultrasound is recommended as the primary screening tool for NTDs, and MSAFP as a secondary screening tool. This is due to increased safety, increased sensitivity and decreased false positive rate of ultrasound as compared to MSAFP. Amniotic fluid alpha-fetoprotein (AFAFP) and amniotic fluid acetylcholinesterase (AFAChE) tests are also used to confirming if ultrasound screening indicates a positive risk. Often, these defects are apparent at birth, but acute defects may not be diagnosed until much later in life. An elevated MSAFP measured at 16–18 weeks gestation is a good predictor of open neural tube defects, however the test has a very high false positive rate, (2% of all women tested in Ontario, Canada between 1993 and 2000 tested positive without having an open neural tube defect, although 5% is the commonly quoted result worldwide) and only a portion of neural tube defects are detected by this screen test (73% in the same Ontario study). MSAFP screening combined with routine ultrasonography has the best detection rate although detection by ultrasonography is dependent on operator training and the quality of the equipment.

The incidence of VACTERL association is estimated to be approximately 1 in 10,000 to 1 in 40,000 live-born infants. It is seen more frequently in infants born to diabetic mothers. While most cases are sporadic, there are clearly families who present with multiple involved members.

Oculofaciocardiodental syndrome is a rare X linked genetic disorder.

Genetic testing methods such as fluorescence in situ hybridization (FISH) and chromosomal microarray are available for diagnosing Dup15q syndrome and similar genetic disorders.

With the increase in genetic testing availability, more often duplications outside of the 15q11.2-13.1 region are being diagnosed. The global chromosome 15q11.2-13.1 duplication syndrome specific groups only provide medical information and research for chromosome 15q11.2-13.1 duplication syndrome and not the outlying 15q duplications.

Zunich–Kaye syndrome, also known as Zunich neuroectodermal syndrome, is a rare congenital ichthyosis first described in 1983. It is also referred to as CHIME syndrome, after its main symptoms (colobomas, heart defects, ichthyosiform dermatosis, intellectual disability, and either ear defects or epilepsy). It is a congenital syndrome with only a few cases studied and published.

Treatment with isotretinoin may induce substantial resolution of skin lesions, but the risk of secondary infection remains.

A diagnosis of pentalogy of Cantrell can often be made before birth (prenatally) sometimes using a fetal ultrasound. An ultrasound is an exam that uses high-frequency sound waves to produce an image of the developing fetus. A fetal ultrasound can detect some of the defects associated with pentalogy of Cantrell. An echocardiography is usually performed to evaluate the extent of the involvement of the heart. An echocardiography is an exam that uses sound waves to produce images of the heart

Magnetic resonance imaging (MRI) may also be performed to assess the degree of certain anomalies such as abdominal wall and pericardial defects. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues.

The four hereditary types of vWD described are type 1, type 2, type 3, and pseudo- or platelet-type. Most cases are hereditary, but acquired forms of vWD have been described. The International Society on Thrombosis and Haemostasis's classification depends on the definition of qualitative and quantitative defects.

In 1996, the United States Food and Drug Administration published regulations requiring the addition of folic acid to enriched breads, cereals, flour and other grain products. It is important to note that during the first four weeks of pregnancy (when most women do not even realize that they are pregnant), adequate folate intake is essential for proper operation of the neurulation process. Therefore, women who could become pregnant are advised to eat foods fortified with folic acid or take supplements in addition to eating folate-rich foods to reduce the risks of serious birth defects.

In Canada, mandatory fortification of selected foods with folic acid has been shown to reduce the incidence of neural tube defects by 46%.

Women who may become pregnant are advised to get 400 micrograms of folic acid daily. Women who have previously given birth to a child with a neural tube defect may benefit from a supplement containing 4.0 mg/5.0 mg in the UK mg daily, following advice provided by their doctor.

22q11.2 deletion syndrome was estimated to affect between one in 2000 and one in 4000 live births. This estimate is based on major birth defects and may be an underestimate, because some individuals with the deletion have few symptoms and may not have been formally diagnosed. It is one of the most common causes of mental retardation due to a genetic deletion syndrome.

The prevalence of 22q11.2DS has been expected to rise because of multiple reasons: (1) Thanks to surgical and medical advances, an increasing number of people are surviving heart defects associated with the syndrome. These individuals are in turn having children. The chances of a 22q11.2DS patient having an affected child is 50% for each pregnancy; (2) Parents who have affected children, but who were unaware of their own genetic conditions, are now being diagnosed as genetic testing become available; (3) Molecular genetics techniques such as FISH (fluorescence in situ hybridization) have limitations and have not been able to detect all 22q11.2 deletions. Newer technologies have been able to detect these atypical deletions.

Recently, the syndrome has been estimated to affect up to one in 2000 live births. Testing for 22q11.2DS in over 9500 pregnancies revealed a prevalence rate of 1/992.

In the middle of the 20th century the principal treatment for some of the amino acid disorders was restriction of dietary protein and all other care was simply management of complications. In the past twenty years, enzyme replacement, gene therapy, and organ transplantation have become available and beneficial for many previously untreatable disorders. Some of the more common or promising therapies are listed: