Differential diagnosis includes Angelman syndrome, Mowat–Wilson syndrome and Rett syndrome.

Diagnosis is made by showing a mutation in the TCF4 gene.

Around 50% of those affected show abnormalities on brain imaging. These include hypoplastic corpus callosum with a missing rostrum and posterior part of the splenium with bulbous caudate nuclei bulging towards the frontal horns.

Electroencephalograms show an excess of slow components.

All have low levels of immunoglobulin M (IgM) but features of an immunodeficiency are absent.

At present, treatment for distal 18q- is symptomatic, meaning the focus is on treating the signs and symptoms of the conditions as they arise. To ensure early diagnosis and treatment, people with distal 18q- are suggested to undergo routine screenings for thyroid, hearing, and vision problems.

Suspicion of a chromosome abnormality is typically raised due to the presence of developmental delays or birth defects. Diagnosis of distal 18q- is usually made from a blood sample. A routine chromosome analysis, or karyotype, is usually used to make the initial diagnosis, although it may also be made by microarray analysis. Increasingly, microarray analysis is also being used to clarify breakpoints. Prenatal diagnosis is possible using amniocentesis or chorionic villus sampling.

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.

Techniques used to diagnose this disorder are fluorescence in situ hybridization (FISH) and microarrays. FISH uses fluorescent dyes to visualize sections under a microscope, but some changes are too small to see. Microarray comparative genomic hybridization (array CGH) shows changes in small amounts DNA on chromosomes.

Diagnosing Jacobsen Syndrome can be difficult in some cases because it is a rare chromosomal disorder. There are a variety of tests that can be carried out like karyotype, cardiac echocardiogram, a renal sonogram, a platelet count, blood count, a brain imaging study. Genetic testing can be carried out for diagnosis. In which chromosomes are stained to give a barcode like appearance and studied under the microscope which reveals the broken and deleted genes. It can also be diagnosed early in the prenatal stage if there are any abnormalities seen in the ultrasound. A simple assessment of the symptoms can be done to diagnose the Syndrome. A thorough physical examination could be carried out to assess the symptoms.

It is possible to clinically detect Alström syndrome in infancy, but more frequently, it is detected much later, as doctors tend to detect symptoms as separate problems. Currently, Alström syndrome is often diagnosed clinically, since genetic testing is costly and only available on a limited basis.

A physical examination would be needed to properly diagnose the patient. Certain physical characteristics can determine if the patient has some type of genetic disorder. Usually, a geneticist would perform the physical examination by measuring the distance around the head, distance between the eyes, and the length of arms and legs. In addition, examinations for the nervous system or the eyes may be performed. Various imaging studies like computerized tomography scans (CT), Magnetic Resonance Imaging (MRI), or X-rays are used to see the structures within the body.

Family and personal medical history are required. Information about the health of an individual is crucial because it provides traces to a genetic diagnosis.

Laboratory tests, particularly genetic testing, are performed to diagnose genetic disorders. Some of the types of genetic testing are molecular, biochemical, and chromosomal. Other laboratory tests performed may measure levels of certain substances in urine and blood that can also help suggest a diagnosis.

Diagnosis involves consideration of physical features and genetic testing. Presence of split uvula is a differentiating characteristic from Marfan Syndrome, as well as the severity of the heart defects. Loeys-Dietz Syndrome patients have more severe heart involvement and it is advised that they be treated for enlarged aorta earlier due to the increased risk of early rupture in Loeys-Dietz patients. Because different people express different combinations of symptoms and the syndrome was identified in 2005, many doctors may not be aware of its existence, although clinical guidelines were released in 2014-2015. Dr. Harold Dietz, Dr. Bart Loeys, and Dr. Kenneth Zahka are considered experts in this condition.

Therapy can help developmental delays, as well as physiotherapy for the low muscle tone. Exercise and healthy eating can reduce weight gain. Treatments are available for seizures, eczema, asthma, infections, and certain bodily ailments.

Suspicion of a chromosome abnormality is typically raised due to the presence of developmental delays or birth defects. Diagnosis of ring 18 is usually made via a blood sample. A routine chromosome analysis, or karyotype, is usually used to make the initial diagnosis, although it may also be made by microarray analysis. Increasingly, microarray analysis is also being used to clarify breakpoints. Prenatal diagnosis is possible via amniocentesis or chorionic villus sampling.

It is suggested that the diagnostic criteria for Malpuech syndrome should include cleft lip and/or palate, typical associated facial features, and at least two of the following: urogenital anomalies, caudal appendage, and growth or developmental delay.

Due to the relatively high rate of hearing impairment found with the disorder, it too may be considered in the diagnosis. Another congenital disorder, Wolf-Hirschhorn (Pitt-Rogers-Danks) syndrome, shares Malpuech features in its diagnostic criteria. Because of this lacking differentiation, karyotyping (microscopic analysis of the chromosomes of an individual) can be employed to distinguish the two. Whereas deletions in the short arm of chromosome 4 would be revealed with Wolf-Hirschhorn, a karyotype without this aberration present would favor a Malpuech syndrome diagnosis. Also, the karyotype of an individual with Malpuech syndrome alone will be normal.

At present, treatment for ring 18 is symptomatic, meaning that the focus is on treating the signs and symptoms of the conditions as they arise. To ensure early diagnosis and treatment, it is suggested that people with ring 18 undergo routine screenings for thyroid, hearing, and vision problems.

Many of the congenital malformations found with Malpuech syndrome can be corrected surgically. These include cleft lip and palate, omphalocele, urogenital and craniofacial abnormalities, skeletal deformities such as a caudal appendage or scoliosis, and hernias of the umbillicus. The primary area of concern for these procedures applied to a neonate with congenital disorders including Malpuech syndrome regards the logistics of anesthesia. Methods like tracheal intubation for management of the airway during general anesthesia can be hampered by the even smaller, or maldeveloped mouth of the infant. For regional anesthesia, methods like spinal blocking are more difficult where scoliosis is present. In a 2010 report by Kiernan et al., a four-year-old girl with Malpuech syndrome was being prepared for an unrelated tonsillectomy and adenoidectomy. While undergoing intubation, insertion of a laryngoscope, needed to identify the airway for the placement of the endotracheal tube, was made troublesome by the presence of micrognathia attributed to the syndrome. After replacement with a laryngoscope of adjusted size, intubation proceeded normally. Successful general anesthesia followed.

A rare follow-up of a male with Malpuech syndrome was presented by Priolo et al. (2007). Born at term from an uneventful pregnancy and delivery, the infant underwent a surgical repair of a cleft lip and palate. No problems were reported with the procedure. A heart abnormality, atrial septal defect, was also apparent but required no intervention. At age three years, mental retardation, hyperactivity and obsessive compulsive disorder were diagnosed; hearing impairment was diagnosed at age six, managed with the use of hearing aids. Over the course of the decade that followed, a number of psychiatric evaluations were performed. At age 14, he exhibited a fear of physical contact; at age 15, he experienced a severe psychotic episode, characterized by agitation and a loss of sociosexual inhibition. This array of symptoms were treated pharmocologically (with prescription medications). He maintained a low level of mental deficiency by age 17, with moments of compulsive echolalia.

As there is no known cure, Loeys–Dietz syndrome is a lifelong condition. Due to the high risk of death from aortic aneurysm rupture, patients should be followed closely to monitor aneurysm formation, which can then be corrected with interventional radiology or vascular surgery.

Previous research in laboratory mice has suggested that the angiotensin II receptor antagonist losartan, which appears to block TGF-beta activity, can slow or halt the formation of aortic aneurysms in Marfan syndrome. A large clinical trial sponsored by the National Institutes of Health is currently underway to explore the use of losartan to prevent aneurysms in Marfan syndrome patients. Both Marfan syndrome and Loeys–Dietz syndrome are associated with increased TGF-beta signaling in the vessel wall. Therefore, losartan also holds promise for the treatment of Loeys–Dietz syndrome. In those patients in which losartan is not halting the growth of the aorta, irbesartan has been shown to work and is currently also being studied and prescribed for some patients with this condition.

If an increased heart rate is present, atenolol is sometimes prescribed to reduce the heart rate to prevent any extra pressure on the tissue of the aorta. Likewise, strenuous physical activity is discouraged in patients, especially weight lifting and contact sports.

The differential diagnosis is quite extensive and includes

- Buschke–Fischer–Brauer disease

- Curth–Macklin ichthyosis

- Gamborg Nielsen syndrome

- Greither disease

- Haber syndrome

- Hereditary punctate palmoplantar keratoderma

- Jadassohn–Lewandowsky syndrome

- Keratosis follicularis spinulosa decalvans

- Keratosis linearis with ichthyosis congenital and sclerosing keratoderma syndrome

- Meleda disease

- Mucosa hyperkeratosis syndrome

- Naegeli–Franceschetti–Jadassohn syndrome

- Naxos disease

- Olmsted syndrome

- Palmoplantar keratoderma and leukokeratosis anogenitalis

- Pandysautonomia

- Papillomatosis of Gougerot and Carteaud

- Papillon–Lefèvre syndrome

- Punctate porokeratotic keratoderma

- Richner–Hanhart syndrome

- Schöpf–Schulz–Passarge syndrome

- Unna Thost disease

- Vohwinkel syndrome

- Wong's dermatomyositis

The use of biochemical testing for the detection of carriers is technically demanding and not often used. Biochemical analyses that have been performed on hair bulbs from at risk women have had a small number of both false positive and false negative outcomes. If only a suspected carrier female is available for mutation testing, it may be appropriate to grow her lymphocytes in 6-thioguanine (a purine analogue), which allows only HGPRT-deficient cells to survive. A mutant frequency of 0.5–5.0 × 10 is found in carrier females, while a non-carrier female has a frequency of 1–20 × 10. This frequency is usually diagnostic by itself.

Molecular genetic testing is the most effective method of testing, as HPRT1 is the only gene known to be associated with LNS. Individuals who display the full Lesch–Nyhan phenotype all have mutations in the HPRT1 gene. Sequence analysis of mRNA is available clinically and can be utilized in order to detect HPRT1 mutations in males affected with Lesch–Nyhan syndrome. Techniques such as RT-PCR, multiplex genomic PCR, and sequence analysis (cDNA and genomic DNA), used for the diagnosis of genetic diseases, are performed on a research basis. If RT-PCR tests result in cDNA showing the absence of an entire exon or exons, then multiplex genomic PCR testing is performed. Multiplex genomic PCR testing amplifies the nine exons of the HPRT1 gene as eight PCR products. If the exon in question is deleted, the corresponding band will be missing from the multiplex PCR. However, if the exon is present, the exon is sequenced to identify the mutation, therefore causing exclusion of the exon from cDNA. If no cDNA is created by RT-PCR, then multiplex PCR is performed on the notion that most or all of the gene is obliterated.

The urate to creatinine (breakdown product of creatine phosphate in muscle) concentration ratio in urine is elevated. This is a good indicator of acid overproduction. For children under ten years of age with LNS, a urate to creatinine ratio above two is typically found. Twenty-four-hour urate excretion of more than 20 mg/kg is also typical but is not diagnostic. Hyperuricemia (serum uric acid concentration of >8 mg/dL) is often present but not reliable enough for diagnosis. Activity of the HGPRT enzyme in cells from any type of tissue (e.g., blood, cultured fibroblasts, or lymphoblasts) that is less than 1.5% of normal enzyme activity confirms the diagnosis of Lesch–Nyhan syndrome. Molecular genetic studies of the HPRT gene mutations may confirm diagnosis, and are particularly helpful for subsequent 'carrier testing' in at-risk females such as close family relatives on the female side.

The diagnosis of Gianotti–Crosti syndrome is clinical. A validated diagnostic criteria is as follows:

A patient is diagnosed as having Gianotti–Crosti syndrome if:

1. On at least one occasion or clinical encounter, he/she exhibits all the positive clinical features,

2. On all occasions or clinical encounters related to the rash, he/she does not exhibit any of the negative clinical features,

3. None of the differential diagnoses is considered to be more likely than Gianotti–Crosti syndrome on clinical judgment, and

4. If lesional biopsy is performed, the histopathological findings are consistent with Gianotti–Crosti syndrome.

The positive clinical features are:

- Monomorphous, flat-topped, pink-brown papules or papulovesicles 1-10mm in diameter.

- At least three of the following four sites involved – (1) cheeks, (2) buttocks, (3) extensor surfaces of forearms, and (4) extensor surfaces of legs.

- Being symmetrical, and

- Lasting for at least ten days.

The negative clinical features are:

- Extensive truncal lesions, and

- Scaly lesions.

Howel–Evans syndrome is an extremely rare condition involving thickening of the skin in the palms of the hands and the soles of the feet (hyperkeratosis). This familial disease is associated with a high lifetime risk of esophageal cancer. For this reason, it is sometimes known as tylosis with oesophageal cancer (TOC).

The condition is inherited in an autosomal dominant manner, and it has been linked to a mutation in the "RHBDF2" gene. It was first described in 1958.

There has been no treatment discovered for Jacobsen Syndrome until now but the Symptoms can be treated. 56% of children with Jacobsen Syndrome have congenital heart problems to keep them in check a baseline evaluation can be made by a paediatric cardiologist by carrying out an electrocardiogram or echocardiogram. Any problems that are found can be treated then.

Almost all affected children are born with a bleeding disorder, monthly CBT may help ease the problem. Consecutively Platelet transfusion and ddAVP can be carried out. Medication that interferes with platelet count should be avoided and oral contraceptive therapy may be considered for women with heavy bleeding during menses.

Children affected with Jacobsen Syndrome have severe to Moderate intellectual disabilities and cognitive impairment. An evaluation by a neuropsychologist or a behaviour specialist like a Psychiatrist or Psychologist can be performed, including brain imaging like MRI or ERP. Then as deemed appropriate intervention programs can be carried through. Music therapy is very beneficial for language development. According to the age, befitting vision and hearing test can aid in fixing problems related cognition. For problems related to behaviour like ADHD, medication or therapy would be required but a combination of both is more effective. An ophthalmologist should be consulted to treat the eye defects. Play and interactive games encourage the child to speak. Habilitiation in children should begin at an early age. A habilitation team includes professionals with special expertise in how disability affects everyday life, health and development. The entire family is supported to help the affected children and their families adjust better.

The presence of dehiscence can be detected by a high definition (0.6 mm or less) coronal CT scan of the temporal bone, currently the most reliable way to distinguish between superior canal dehiscence syndrome (SCDS) and other conditions of the inner ear involving similar symptoms such as Ménière's disease and perilymphatic fistula. Other diagnostic tools include the vestibular evoked myogenic potential or VEMP test, videonystagmography (VNG), electrocochleography (ECOG) and the rotational chair test. An accurate diagnosis is of great significance as unnecessary exploratory middle ear surgery may thus be avoided. Several of the symptoms typical to SCDS (e.g. vertigo and Tullio) may also be present singly or as part of Ménière's disease, sometimes causing the one illness to be confused with the other. There are reported cases of patients being affected by both Ménière's disease and SCDS concurrently.

As SCDS is a very rare and still a relatively unknown condition, obtaining an accurate diagnosis of this distressing (and even disabling) disease may take some time as many health care professionals are not yet aware of its existence.

Once diagnosed, the gap in the temporal bone can be repaired by surgical resurfacing of the affected bone or plugging of the superior semicircular canal. These techniques are performed by accessing the site of the dehiscence either via a middle fossa craniotomy or via a canal drilled through the transmastoid bone behind the affected ear. Bone cement has been the material most often used, in spite of its tendency to slippage and resorption, and a consequent high failure rate; recently, soft tissue grafts have been substituted.

There are at least four types of FFDD:

- Type I: autosomal dominant FFDD

- Type II: autosomal recessive FFDD

- Type III: FFDD with other facial features

- Type IV: facial lesions resembling aplasia cutis in a preauricular distribution along the line of fusion of the maxillary and mandibular prominences. Autosomal recessive.

The differential diagnoses are: acrodermatitis enteropathica, erythema infectiosum, erythema multiforme, hand-foot-and-mouth disease, Henoch–Schönlein purpura, Kawasaki disease, lichen planus, papular urticaria, papular purpuric gloves and socks syndrome, and scabies.