If the diagnosis is suspected, serology can be performed:

- One test is for antibodies against the acetylcholine receptor; the test has a reasonable sensitivity of 80–96%, but in ocular myasthenia, the sensitivity falls to 50%.

- A proportion of the patients without antibodies against the acetylcholine receptor have antibodies against the MuSK protein.

- In specific situations, testing is performed for Lambert-Eaton syndrome.

A chest X-ray may identify widening of the mediastinum suggestive of thymoma, but computed tomography or magnetic resonance imaging (MRI) are more sensitive ways to identify thymomas and are generally done for this reason. MRI of the cranium and orbits may also be performed to exclude compressive and inflammatory lesions of the cranial nerves and ocular muscles.

The diagnosis is usually made on electromyography (EMG), which is one of the standard tests in the investigation of otherwise unexplained muscle weakness. This involves the insertion of small needles into the nerves supplying several muscles, administering small electrical impulses through these needles, and measuring the electrical response of the muscle in question. Two EMG investigations can be characteristic in LEMS: compound motor action potentials (CMAPs) and single-fiber examination.

CMAPs show small amplitudes but normal latency and conduction velocities. If repeated impulses are administered (2 per second or 2 Hz), it is normal for CMAP amplitudes to become smaller as the acetylcholine in the motor end plate is depleted. In LEMS, this decrease is larger than observed normally. Eventually, stored acetylcholine is made available, and the amplitudes increase again. In LEMS, this remains insufficient to reach a level sufficient for transmission of an impulse from nerve to muscle; all can be attributed to insufficient calcium in the nerve terminal. A similar pattern is witnessed in myasthenia gravis. In LEMS, in response to exercising the muscle, the CMAP amplitude increases greatly (over 200%, often much more). This also occurs on the administration of a rapid burst of electrical stimuli (20 impulses per second for 10 seconds). This is attributed to the influx of calcium in response to these stimuli. On single-fiber examination, features may include increased jitter (seen in other diseases of neuromuscular transmission) and blocking.

Blood tests may be performed to exclude other causes of muscle disease (elevated creatine kinase may indicate a myositis, and abnormal thyroid function tests may indicate thyrotoxic myopathy). Antibodies against voltage-gated calcium channels can be identified in 85% of people with EMG-confirmed LEMS. Once LEMS is diagnosed, investigations such as a CT scan of the chest are usually performed to identify any possible underlying lung tumors. Around 50–60% of these are discovered immediately after the diagnosis of LEMS. The remainder is diagnosed later, but usually within two years and typically within four years. As a result, scans are typically repeated every six months for the first two years after diagnosis. While CT of the lungs is usually adequate, a positron emission tomography scan of the body may also be performed to search for an occult tumour, particularly of the lung.

This condition can be diagnosed by genetic testing. Furthermore, an echocardiogram and X-ray may help in the diagnosis.

The differential diagnosis of this condition consists of:

- Hypertrophic cardiomyopathy

- Beckwith-Wiedemann syndrome

- Berardinelli-Seip congenital lipodystrophy

If LEMS is caused by an underlying cancer, treatment of the cancer usually leads to resolution of the symptoms. Treatment usually consists of chemotherapy, with radiation therapy in those with limited disease.

Neurotoxin may act on the neuromuscular junction either post synaptically or presynaptically as there are several different forms of toxins that the NMJ is sensitive to.(reference 14) Common mechanisms of action include blockage of acetylcholine release at the synapse thus causing the NMJ to become abnormal in function.(reference 12)

Genetic testing for CHARGE syndrome involves specific genetic testing for the CHD7 gene. The test is available at most major genetic testing laboratories. Insurance companies sometimes do not pay for such genetic tests, though this is changing rapidly as genetic testing is becoming standard across all aspects of medicine. CHARGE syndrome is a clinical diagnosis, which means genetic testing is not required in order to make the diagnosis. Rather, the diagnosis can be made based on clinical features alone.

Currently there are no official tests or treatments for ROHHAD. Each child has the symptoms above at different ages, yet most symptoms are eventually present. Many children are misdiagnosed or are never diagnosed until alveolar hypoventilation occurs.

Congenital syndromes affecting the neuromuscular junction are considered a very rare form of disease, occurring in 1 out of 200,000 in the United Kingdom.(reference 29) These are genetically inherited disorders. Symptoms are seen early since the affected individuals carry the mutation from birth. Congenital syndromes are usually classified by the location of the affected gene products. Congenital syndromes can have multiple targets affecting either the presynaptic, synaptic or postsynaptic parts of the neuromuscular junction.(reference 30) For example, if the malfunctioning or inactive protein is acetylcholinesterase, this would be classified as a synapse congenital syndrome.(reference 29)

Laboratory investigations usually show elevated creatine kinase, myopathic/dystrophic muscle pathology and altered α-dystroglycan. Antenatal diagnosis is possible in families with known mutations. Prenatal ultrasound may be helpful for diagnosis in families where the molecular defect is unknown.

Once the diagnosis is made based on clinical signs, it is important to investigate other body systems that may be involved. For example, if the diagnosis is made based on the abnormal appearance of the ears and developmental delay, it is important to check the child's hearing, vision, heart, nose, and urogenital system. Ideally, every child newly diagnosed with CHARGE syndrome should have a complete evaluation by an ENT specialist, audiologist, ophthalmologist, pediatric cardiologist, developmental therapist, and pediatric urologist.

CCD may be detectable on prenatal ultrasound. After birth, signs in affected babies typically are abdominal distension, visible peristalsis, and watery stools persistent from birth that show chloride loss of more than 90 mmol/l.

An important feature in this diarrhea that helps in the diagnosis, is that it is the only type of diarrhea that causes metabolic alkalosis rather than metabolic acidosis.

The only treatment for MWS is only symptomatic, with multidisciplinary management

A 2007 study followed 112 individuals for a mean of 12 years (mean age 25.3, range 12–71). No patient died during follow-up, but several required medical interventions. The mean final heights were 167 and 153 cm for men and women, respectively, which is approximately 2 standard deviations below normal.

There have been 30 cases of Marden-Walker Syndrome reported since 1966. The first case of this was in 1966 a female infant was diagnosed with blepharophimosis, joint contractures, arachnodactyly and growth development delay. She ended up passing at 3 months due to pneumonia.

Diagnosis of MSS is based on clinical symptoms, magnetic resonance imaging (MRI) of the brain (cerebellar atrophy particularly involving the cerebellar vermis), and muscle biopsy.

It can be associated with mutations of the SIL1 gene, and a mutation can be found in about 50% of cases.

Differential diagnosis includes Congenital Cataracts Facial Dysmorphism Neuropathy (CCFDN), Marinesco–Sjögren like syndrome with chylomicronemia, carbohydrate deficient glycoprotein syndromes, Lowe syndrome, and mitochondrial disease.

Prenatal Diagnosis:

- Aymé, "et al." (1989) reported prenatal diagnosis of Fryns syndrome by sonography between 24 and 27 weeks.

- Manouvrier-Hanu et al. (1996) described the prenatal diagnosis of Fryns syndrome by ultrasonographic detection of diaphragmatic hernia and cystic hygroma. The diagnosis was confirmed after termination of the pregnancy. The fetus also had 2 erupted incisors; natal teeth had not been mentioned in other cases of Fryns syndrome.

Differential Diagnosis:

- McPherson et al. (1993) noted the phenotypic overlap between Fryns syndrome and the Pallister–Killian syndrome (601803), which is a dysmorphic syndrome with tissue-specific mosaicism of tetrasomy 12p.

- Veldman et al. (2002) discussed the differentiation between Fryns syndrome and Pallister–Killian syndrome, noting that differentiation is important to genetic counseling because Fryns syndrome is an autosomal recessive disorder and Pallister–Killian syndrome is usually a sporadic chromosomal aberration. However, discrimination may be difficult due to the phenotypic similarity. In fact, in some infants with 'coarse face,' acral hypoplasia, and internal anomalies, the initial diagnosis of Fryns syndrome had to be changed because mosaicism of isochromosome 12p was detected in fibroblast cultures or kidney tissue. Although congenital diaphragmatic hernia is a common finding in both syndromes, bilateral congenital diaphragmatic hernia had been reported only in patients with Fryns syndrome until the report of the patient with Pallister–Killian syndrome by Veldman et al. (2002).

- Slavotinek (2004) reviewed the phenotypes of 52 reported cases of Fryns syndrome and reevaluated the diagnostic guidelines. She concluded that congenital diaphragmatic hernia and distal limb hypoplasia are strongly suggestive of Fryns syndrome, with other diagnostically relevant findings including pulmonary hypoplasia, craniofacial dysmorphism, polyhydramnios, and orofacial clefting. Slavotinek (2004) stated that other distinctive anomalies not mentioned in previous guidelines include ventricular dilatation or hydrocephalus, agenesis of the corpus callosum, abnormalities of the aorta, dilatation of the ureters, proximal thumbs, and broad clavicles.

NS can be confirmed genetically by the presence of any of the known mutations listed above. However, despite identification of fourteen causative genes, the absence of a known mutation will not exclude the diagnosis, as there are more, as-yet-undiscovered genes that cause NS. Thus, the diagnosis of NS is still based on clinical features. In other words, it is made when a physician feels that a patient has enough of the features to warrant the label. The principal values of making a genetic diagnosis are that it guides additional medical and developmental evaluations, it excludes other possible explanations for the features, and it allows more accurate recurrence risk estimates. With more genotype-phenotype correlation studies being performed, a positive genetic diagnosis will help the clinician to be aware of possible anomalies specific to that certain gene mutation. For example, there is an increase in hypertrophic cardiomyopathy in patients with a mutation of "KRAS" and an increased risk of juvenile myelomonocytic leukemia for a mutation of "PTPN11". In the future, studies may lead to a targeted management of NS symptoms that depends on what genetic mutation a patient has.

Radiologic diagnosis

The differential diagnosis of congenital hyperinsulinism is consistent with PMM2-CDG, as well as several syndromes. Among other DDx we find the following that are listed:

- MPI-CDG

- Beckwith-Wiedemann syndrome

- Sotos syndrome

- Usher 1 syndromes

In terms of the investigation of congenital hyperinsulinism, valuable diagnostic information is obtained from a blood sample drawn during hypoglycemia, detectable amounts of insulin during hypoglycemia are abnormal and indicate that hyperinsulinism is likely to be the cause. Inappropriately low levels of free fatty acids and ketones provide additional evidence of insulin excess. An additional piece of evidence indicating hyperinsulinism is a usually high requirement for intravenous glucose to maintain adequate glucose levels, the minimum glucose required to maintain a plasma glucose above 70 mg/dl. A GIR above 8 mg/kg/minute in infancy suggests hyperinsulinism. A third form of evidence suggesting hyperinsulinism is a rise of the glucose level after injection of glucagon at the time of the low glucose.

Diagnostic efforts then shift to determining the type- elevated ammonia levels or abnormal organic acids can indicate specific, rare types. Intrauterine growth retardation and other perinatal problems raise the possibility of transience, while large birthweight suggests one of the more persistent conditions. Genetic screening is now available within a useful time frame for some of the specific conditions.It is worthwhile to identify the minority of severe cases with focal forms of hyperinsulinism because these can be completely cured by partial pancreatectomy. A variety of pre-operative diagnostic procedures have been investigated but none has been established as infallibly reliable. Positron emission tomography is becoming the most useful imaging technique.

In terms of the diagnosis of arterial tortuosity syndrome can be done via genetic testing, as well as the following listed below:

- CT

- MRI

- Echocardiogram

- Physical exam(for specific characteristics)

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.

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.

There is no known cure for this syndrome. Patients usually need ophthalmic surgery and may also need dental surgery

Genetic counseling and screening of the mother's relatives is recommended.