The clinical diagnosis is backed up by investigative findings. Citrulline level in blood is decreased. Mitochondrial studies or NARP mtDNA evaluation plays a role in genetic diagnosis which can also be done prenatally.

The severity and prognosis vary with the type of mutation involved.

Screening generally only takes place among those displaying several of the symptoms of ABCD, but a study on a large group of institutionalized deaf people in Columbia revealed that 5.38% of them were Waardenburg patients. Because of its rarity, none of the patients were diagnosed with ABCD (Waardenburg Type IV). Nothing can be done to prevent the disease.

The occurrence of WS has been reported to be one in 45,000 in Europe. The diagnosis can be made prenatally by ultrasound due to the phenotype displaying pigmentary disturbances, facial abnormalities, and other developmental defects. After birth, the diagnosis is initially made symptomatically and can be confirmed through genetic testing. If the diagnosis is not made early enough, complications can arise from

Hirschsprung's disease.

Mitochondrial diseases are usually detected by analysing muscle samples, where the presence of these organelles is higher. The most common tests for the detection of these diseases are:

1. Southern blot to detect big deletions or duplications

2. PCR and specific mutation analysis

3. Sequencing

Diagnosis of oculocerebrorenal syndrome can be done via genetic testing Among the different investigations that can de done are:

- Urinalysis

- MRI

- Blood test

Since Usher syndrome is incurable at present, it is helpful to diagnose children well before they develop the characteristic night blindness. Some preliminary studies have suggested as many as 10% of congenitally deaf children may have Usher syndrome. However, a misdiagnosis can have bad consequences.

The simplest approach to diagnosing Usher syndrome is to test for the characteristic chromosomal mutations. An alternative approach is electroretinography, although this is often disfavored for children, since its discomfort can also make the results unreliable. Parental consanguinity is a significant factor in diagnosis. Usher syndrome I may be indicated if the child is profoundly deaf from birth and especially slow in walking.

Thirteen other syndromes may exhibit signs similar to Usher syndrome, including Alport syndrome, Alstrom syndrome, Bardet-Biedl syndrome, Cockayne syndrome, spondyloepiphyseal dysplasia congenita, Flynn-Aird syndrome, Friedreich ataxia, Hurler syndrome (MPS-1), Kearns-Sayre syndrome (CPEO), Norrie syndrome, osteopetrosis (Albers-Schonberg disease), Refsum's disease (phytanic acid storage disease), and Zellweger syndrome (cerebrohepatorenal syndrome).

Carrier testing for Roberts syndrome requires prior identification of the disease-causing mutation in the family. Carriers for the disorder are heterozygotes due to the autosomal recessive nature of the disease. Carriers are also not at risk for contracting Roberts syndrome themselves. A prenatal diagnosis of Roberts syndrome requires an ultrasound examination paired with cytogenetic testing or prior identification of the disease-causing ESCO2 mutations in the family.

Since Usher syndrome results from the loss of a gene, gene therapy that adds the proper protein back ("gene replacement") may alleviate it, provided the added protein becomes functional. Recent studies of mouse models have shown one form of the disease—that associated with a mutation in myosin VIIa—can be alleviated by replacing the mutant gene using a lentivirus. However, some of the mutated genes associated with Usher syndrome encode very large proteins—most notably, the "USH2A" and "GPR98" proteins, which have roughly 6000 amino-acid residues. Gene replacement therapy for such large proteins may be difficult.

Spindle transfer, where the nuclear DNA is transferred to another healthy egg cell leaving the defective mitochondrial DNA behind, is a potential treatment procedure that has been successfully carried out on monkeys. Using a similar pronuclear transfer technique, researchers at Newcastle University led by Douglass Turnbull successfully transplanted healthy DNA in human eggs from women with mitochondrial disease into the eggs of women donors who were unaffected. In such cases, ethical questions have been raised regarding biological motherhood, since the child receives genes and gene regulatory molecules from two different women. Using genetic engineering in attempts to produce babies free of mitochondrial disease is controversial in some circles and raises important ethical issues. A male baby was born in Mexico in 2016 from a mother with Leigh syndrome using spindle transfer.

In September 2012 a public consultation was launched in the UK to explore the ethical issues involved. Human genetic engineering was used on a small scale to allow infertile women with genetic defects in their mitochondria to have children.

In June 2013, the United Kingdom government agreed to develop legislation that would legalize the 'three-person IVF' procedure as a treatment to fix or eliminate mitochondrial diseases that are passed on from mother to child. The procedure could be offered from 29 October 2015 once regulations had been established.

Embryonic mitochondrial transplant and protofection have been proposed as a possible treatment for inherited mitochondrial disease, and allotopic expression of mitochondrial proteins as a radical treatment for mtDNA mutation load.

Currently, human clinical trials are underway at GenSight Biologics (ClinicalTrials.gov # NCT02064569) and the University of Miami (ClinicalTrials.gov # NCT02161380) to examine the safety and efficacy of mitochondrial gene therapy in Leber's hereditary optic neuropathy.

In terms of treatment of oculocerebrorenal syndrome for those individuals who are affected by this condition includes the following:

- Glaucoma control (via medication)

- Nasogastric tube feeding

- Physical therapy

- Clomipramine

- Potassium citrate

Genetic testing may be available for mutations in the FGDY1 gene. Genetic counseling is indicated for individuals or families who may carry this condition, as there are overlapping features with fetal alcohol syndrome.

Other examinations or tests can help with diagnosis. These can include:

detailed family history

- conducting a detailed physical examination to document morphological features

- testing for genetic defect in FGDY1

- x-rays can identify skeletal abnormalities

- echo cardiogram can screen for heart abnormalities

- CT scan of the brain for cystic development

- X-ray of the teeth

- Ultrasound of abdomen to identify undescended testis

Diagnosis is made based on features as well as by the very early onset of serious eye and ear disease. Because Marshall syndrome is an autosomal dominant hereditary disease, physicians can also note the characteristic appearance of the biological parent of the child. There are no tests for Stickler syndrome or Marshall syndrome. Some families with Stickler syndrome have been shown to have mutations in the Type II collagen gene on chromosome 1. However, other families do not show the linkage to the collagen gene. It is an area of active research, also the genetic testing being expensive supports that the diagnosis is made depending on the features.

Cytogenetic preparations that have been stained by either Giemsa or C-banding techniques will show two characteristic chromosomal abnormalities. The first chromosomal abnormality is called premature centromere separation (PCS) and is the most likely pathogenic mechanism for Roberts syndrome. Chromosomes that have PCS will have their centromeres separate during metaphase rather than anaphase (one phase earlier than normal chromosomes). The second chromosomal abnormality is called heterochromatin repulsion (HR). Chromosomes that have HR experience separation of the heterochromatic regions during metaphase. Chromosomes with these two abnormalities will display a "railroad track" appearance because of the absence of primary constriction and repulsion at the heterochromatic regions. The heterochromatic regions are the areas near the centromeres and nucleolar organizers. Carrier status cannot be determined by cytogenetic testing. Other common findings of cytogenetic testing on Roberts syndrome patients are listed below.

- Aneuploidy- the occurrence of one or more extra or missing chromosomes

- Micronucleation- nucleus is smaller than normal

- Multilobulated Nuclei- the nucleus has more than one lobe

Bloom syndrome is diagnosed using any of three tests - the presence of quadriradial (Qr, a four-armed chromatid interchange) in cultured blood lymphocytes, and/or the elevated levels of Sister chromatid exchange in cells of any type, and/or the mutation in the BLM gene. The US Food and Drug Administration (FDA) announced on February 19, 2015 that they have authorized marketing of a direct-to-consumer genetic test from 23andMe. The test is designed to identify healthy individuals who carry a gene that could cause Bloom Syndrome in their offspring.

Many professionals that are likely to be involved in the treatment of those with Stickler's syndrome, include anesthesiologists, oral and maxillofacial surgeons; craniofacial surgeons; ear, nose, and throat specialists, ophthalmologists, optometrists, audiologists, speech pathologists, physical therapists and rheumatologists.

There is no medical treatment for either syndrome but there are some recommendations that can help with prevention or early identification of some of the problems. Children with either syndrome should have their hearing tested, and adults should be aware that the hearing loss may not develop until the adult years. Yearly visits to an ophthalmologist or other eye care professional who has been informed of the diagnosis of Stickler or Marshall syndrome is important for all affected individuals. Children should have the opportunity to have myopia corrected as early as possible, and treatment for cataracts or detached retinas may be more effective with early identification. Support for the joints is especially important during sports, and some recommend that contact sports should be avoided by those who have very loose joints.

Bloom syndrome has no specific treatment; however, avoiding sun exposure and using sunscreens can help prevent some of the cutaneous changes associated with photo-sensitivity. Efforts to minimize exposure to other known environmental mutagens are also advisable.

Diagnosis depends on the clinical scenario. However, karyotyping is an essential test for diagnosis.

Diagnosis of Harlequin syndrome is made when the individual has consistent signs and symptoms of the condition, therefore, it is made by clinical observation. In addition, a neurologist or primary care physician may require an MRI test to rule out similar disorders such as Horner's syndrome, Adie's syndrome, and Ross' syndrome. In an MRI, a radiologist may observe areas near brain or spinal cord for lesions, or any damage to the nerve endings. It is also important that the clinician rules out traumatic causes by performing autonomic function tests. Such tests includes the following: tilt table test, orthostatic blood pressure measurement, head-up test, valsalva maneuver, thermoregulatory sweat test, tendon reflex test, and electrocardiography (ECG). CT scan of the heart and lungs may also be performed to rule out a structural underlying lesion. The medical history of the individual should be carefully noted.

Genetic changes are related to the following types of Stickler syndrome:

- Stickler syndrome, COL2A1 (75% of Stickler cases)

- Stickler syndrome, COL11A1

- Stickler syndrome, COL11A2 (non-ocular)

- Stickler syndrome, COL9A1 (recessive variant)

Whether there are two or three types of Stickler syndrome is controversial. Each type is presented here according to the gene involved. The classification of these conditions is changing as researchers learn more about the genetic causes.

Orofaciodigital syndrome type 1 is diagnosed through genetic testing. Some symptoms of Orofaciodigital syndrome type 1 are oral features such as, split tongue, benign tumors on the tongue, cleft palate, hypodontia and other dental abnormalities. Other symptoms of the face include hypertelorism and micrognathia. Bodily abnormalities such as webbed, short, joined, or abnormally curved fingers and toes are also symptoms of Orofaciodigital syndrome type 1. The most frequent symptoms are accessory oral frenulum, broad alveolar ridges, frontal bossing, high palate, hypertelorism, lobulated tongue, median cleft lip, and wide nasal bridge. Genetic screening of the OFD1 gene is used to officially diagnose a patient who has the syndrome, this is detected in 85% of individuals who are suspected to have Orofaciodigital syndrome type 1.

Diagnosis can be made by EEG. In case of epileptic spasms, EEG shows typical patterns.

The diagnosis of this syndrome can be made on clinical examination and perinatal autopsy.

Koenig and Spranger (1986) noted that eye lesions are apparently nonobligatory components of the syndrome. The diagnosis of Fraser syndrome should be entertained in patients with a combination of acrofacial and urogenital malformations with or without cryptophthalmos. Thomas et al. (1986) also emphasized the occurrence of the cryptophthalmos syndrome without cryptophthalmos and proposed diagnostic criteria for Fraser syndrome. Major criteria consisted of cryptophthalmos, syndactyly, abnormal genitalia, and positive family history. Minor criteria were congenital malformation of the nose, ears, or larynx, cleft lip and/or palate, skeletal defects, umbilical hernia, renal agenesis, and mental retardation. Diagnosis was based on the presence of at least 2 major and 1 minor criteria, or 1 major and 4 minor criteria.

Boyd et al. (1988) suggested that prenatal diagnosis by ultrasound examination of eyes, digits, and kidneys should detect the severe form of the syndrome. Serville et al. (1989) demonstrated the feasibility of ultrasonographic diagnosis of the Fraser syndrome at 18 weeks' gestation. They suggested that the diagnosis could be made if 2 of the following signs are present: obstructive uropathy, microphthalmia, syndactyly, and oligohydramnios. Schauer et al. (1990) made the diagnosis at 18.5 weeks' gestation on the basis of sonography. Both the female fetus and the phenotypically normal father had a chromosome anomaly: inv(9)(p11q21). An earlier born infant had Fraser syndrome and the same chromosome 9 inversion.

Van Haelst et al. (2007) provided a revision of the diagnostic criteria for Fraser syndrome according to Thomas et al. (1986) through the addition of airway tract and urinary tract anomalies to the major criteria and removal of mental retardation and clefting as criteria. Major criteria included syndactyly, cryptophthalmos spectrum, urinary tract abnormalities, ambiguous genitalia, laryngeal and tracheal anomalies, and positive family history. Minor criteria included anorectal defects, dysplastic ears, skull ossification defects, umbilical abnormalities, and nasal anomalies. Cleft lip and/or palate, cardiac malformations, musculoskeletal anomalies, and mental retardation were considered uncommon. Van Haelst et al. (2007) suggested that the diagnosis of Fraser syndrome can be made if either 3 major criteria, or 2 major and 2 minor criteria, or 1 major and 3 minor criteria are present in a patient.

Liver function tests are normal. Pigmented granules are not seen in the hepatocytes of individuals with Rotor syndrome.