Initially, patients with neonatal or early-childhood onset diabetes are possible candidates for having Wolcott–Rallison syndrome. The other symptoms include the multiple epiphyseal dysplasia, osteopenia, intellectual disability, and hepatic and renal dysfunction. Patients with the symptoms that line up with Wolcott–Rallison syndrome can be suggested for genetics testing. The key way to test for this disease specifically is through genetic testing for the EIKF2AK3 mutation. Molecular genetic analysis can be done for the patient and the parents to test for de novo mutations or inherited. It can also show whether the patient's parents are heterozygotes or homozygotes for the normal phenotype. X-Rays can show bone age in relation to actual age. Typically the bond age is a few years less than the actual in the patients with WRS. Hypothyroidism is rare is WRS patients but can occur.

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.

Infants with DG who drink breast milk or lactose-containing formula may have elevated levels of galactose in their blood, tissues, and urine due to their impaired ability to process the galactose after it has been absorbed. DG can be detected in dried blood spots by newborn screening on the basis of elevated galactose metabolite levels, low GALT enzyme activity, or both. DG can be diagnosed by genetic testing.

Not all NBS tests for galactosemia are designed to detect DG so affected infants born in one location may be detected while those born in another may not. For example, all states in the US screen for classic galactosemia in their NBS panel, but some states have lower GALT enzyme activity cut-off levels than others. NBS in states with a low GALT cut off level still detects classic galactosemia and helps to minimize false positives, but it can also result in "missed" DG diagnoses for those samples with partial GALT enzyme activity that is above the cut-off. In those states, a NBS result for galactosemia designated as "normal" may not be informative about an infant's DG status.

Most infants with DG who are detected by NBS have their diagnosis confirmed in a follow-up evaluation. The differential diagnosis of a positive newborn screen for galactosemia includes: classic galactosemia, clinical variant galactosemia, DG, GALE (epimerase) deficiency, GALK (galactokinase) deficiency, or an initial false positive result. There are also other rare conditions, such as portosystemic venous shunting and hepatic arteriovenous malformations, or Fanconi-Bickel Syndrome (GSDXI) that can lead to elevated blood galactose or urinary galactitol, triggering an initial suspicion of galactosemia.

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 of TNDM and PNDM

The diagnostic evaluations are based upon current literature and research available on NDM. The following evaluation factors are: patients with TNDM are more likely to have intrauterine growth retardation and less likely to develop ketoacidosis than patients with PNDM. TNDM patients are younger at the age of diagnosis of diabetes and have lower insulin requirements, an overlap occurs between the two groups, therefore TNDM cannot be distinguished from PNDM based clinical feature. An early onset of diabetes mellitus is unrelated to autoimmunity in most cases, relapse of diabetes is common with TNDM, and extensive follow ups are important. In addition, molecular analysis of chromosomes 6 defects, KCNJ11 and ABCC8 genes (encoding Kir6.2 and SUR1) provide a way to identify PNDM in the infant stages. Approximately,50% of PNDM are associated with the potassium channel defects which are essential consequences when changing patients from insulin therapy to sulfonylureas.

TNDM Diagnosis associated with Chromosome 6q24 Mutations

The uniparental disomy of the chromosome can be used as diagnostic method provide proof by the analysis of polymorphic markers is present on Chromosome 6. Meiotic segregation of the chromosome can be distinguished by comparing allele profiles of polymorphic makers in the child to the child's parents' genome. Normally, a total uniparental disomy of the chromosome 6 is evidenced, but partial one can be identified. Therefore, genetic markers that are close to the region of interest in chromosome 6q24 can be selected. Chromosome duplication can found by that technique also.

Medical Professionals of NDM

- Physician

- Endocrinologist

- Geneticist Counselor

Diagnostic Test of NDM

- "Fasting plasma glucose test": measures an diabetic's blood glucose after he or she has gone 8 hours without eat. This test is used to detect diabetes or pre-diabetes

- "Oral glucose tolerance test"- measures an individual's blood glucose after he or she have gone at least 8 hours without eating and two hours after the diabetic individual have drunk a glucose-containing beverage. This test can be used to diagnose diabetes or pre-diabetes

- "Random plasma glucose test"-the doctor checks one's blood glucose without regard to when an individual may have ate his or her last meal. This test, along with an evaluation of symptoms, are used to diagnose diabetes but not pre-diabetes.

Genetic Testing of NDM

- "Uniparental Disomy Test:"

Samples from fetus or child and both parents are needed for analysis. Chromosome of interest must be specified on request form. For prenatal samples (only): if the amniotic fluid (non-confluent culture cells) are provided. Amniotic fluid is added and charged separately. Also, if chorionic villus sample is provided, a genetic test will be added and charged separately. Microsatellites markers and polymerase chain reaction are used on the chromosomes of interest to test the DNA of the parent and child to identify the presence of uni"parental disomy""."

- Intrauterine Growth Restriction

"Apgar score is" a test given after birth to test the baby's physical condition and evaluate if special medical care is needed.

The most common method to manage hypoglycemia and diabetes is with an insulin pump. . However in infants and very young children long acting insulins like Glargine and Levemir are preferred to prevent recurrent hypoglycemia . As soon as parent knows Walcott-Rallison syndrome is the source, treatment or therapy plans need to be drawn up along with frequent check ins to make sure kidney and liver functions are around normal and insulin therapy are working. If needed, the patient can undergo thyroxin therapy in order to maintain proper thyroid stimulating hormone levels. This has only been needed in a few cases were hypothyroidism was present in the patient.

Very little is known about outcomes in DG after early childhood. This is because many infants with DG are born in states where they are not diagnosed by NBS, and of those who are diagnosed, most are discharged from metabolic follow-up as toddlers.

Because it is unclear whether DG has any long-term developmental impacts, or if diet modification would prevent or resolve any issues that may result from DG, any developmental or psychosocial problems experienced by a person with DG should be treated symptomatically and the possibility of other causes should be explored.

Of note, premature ovarian insufficiency, a common outcome among girls and women with classic galactosemia, has been checked by hormone studies and does not appear to occur at high prevalence among girls with DG.

Prior Research Concerning Developmental Outcomes of Children with DG: Three

studies of developmental outcomes of children with DG have been published.

- The first looked at biochemical markers and developmental outcomes in a group of 28 toddlers and young children with DG, some of whom had drunk milk through infancy and some of whom had drunk soy formula. The authors found that galactose metabolites were significantly elevated in the infants drinking milk over those drinking soy. However, all of the children scored within normal limits on standardized tests of child development.

- A second study of developmental outcomes in DG looked at 3 to 10 year olds living in a large metropolitan area and asked whether children diagnosed as newborns with DG in this group were more likely than their unaffected peers to receive special educational services later in childhood. The answer was yes. Specifically, children with DG in this group were significantly more likely than other children to receive a diagnosis of, or special educational services for, a speech/language disorder.

- The final study reported that addressed developmental outcomes in DG was a pilot study involving direct assessments of 15 children, all ages 6–11 years old; 15 had DG and 5 did not. Children in the DG group showed slower auditory processing than did the control group. The DG group also showed some slight differences in auditory memory, receptive language/ listening skills, social-emotional functioning, and balance and fine motor coordination.

Combined,

these studies "suggest" that school age

children with DG "might" be at

increased risk for specific developmental difficulties compared with controls. All

of the relevant studies were limited, however, leaving the question of whether

children with DG are truly at increased risk for developmental difficulties

unresolved. Current reports also leave open the question of whether dietary

exposure to milk in infancy associates with developmental outcomes in DG. More

research is needed to answer these questions.

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

- Urinalysis

- MRI

- Blood test

Physical examination findings in patients with CDGP are essentially normal, with the exception of immature appearance for age. Body proportions may reflect the delay in growth. During childhood, the upper-to-lower body ratio may be greater than normal, reflecting more infantile proportions. In adults, the ratio is often reduced (i.e., <1 in whites, <0.9 in blacks) as a result of the longer period of leg (long bone) growth.

CDGP is thought to be inherited from multiple genes from both parents. The strong role of heredity is reflected in the 60-90% likelihood of this growth pattern in a family member of the same or opposite sex. A delay in the reactivation of the hypothalamic-pituitary pulse generator results in a later onset of puberty.

Causes of NDM

PNDM and TNDM are inherited genetically from the mother or father of the infant. Different genetic inheritance or genetic mutations can lead to different diagnosis of NDM (Permanent or Transient Neonatal Diabetes Mellitus). The following are different types of inheritance or mutations:

- "Autosomal Dominant": Every cell has two copies of each gene-one gen coming from the mother and one coming from the father. Autosomal dominant inheritance pattern is defined as a mutation that occurs in only one copy of the gene. A parent with the mutation can pass on a copy of the gene and a parent with the mutation can pass on a copy of their working gene (or a copy of their damaged gene). In an autosomal dominant inheritance, a child who has a parent with the mutation has a 50% possibility of inheriting the mutation.

- "Autosomal Recessive" -Autosomal recessive-Generally, every cells have two copies of each gene-one gene is inherited from the mother and one gene is inherited from the father. Autosomal recessive inheritance pattern is defined as a mutation present in both copies if the gene in order for a person to be affected and each parent much pass on a mutated gene for a child to be affected. However, if an infant or child has only one copy, he or she are a carrier of the mutation. If moth parents are carriers of the recessive gene mutation, each child have a 25% chance of inheriting the gene.

- "Spontaneous": A new mutation or change occurs within the gene.

- "X-linked:" When a trait or disease happens in a person who has inherited a mutated gene on the X chromosome (one of the sex chromosome).

Prevention: There are no current prevention methods, because TNDM or PNDM are inherited genetically.

Research for designing therapeutic trials is ongoing via the Washington University Wolfram Study Group, supported by The Ellie White Foundation for Rare Genetic Disorders and The Jack and J.T. Snow Scientific Research Foundation for Wolfram research.

The first symptom is typically diabetes mellitus, which is usually diagnosed around the age of 6. The next symptom to appear is often optic atrophy, the wasting of optic nerves, around the age of 11. The first signs of this are loss of colour vision and peripheral vision. The condition worsens over time, and people with optic atrophy are usually blind within 8 years of the first symptoms. Life expectancy of people suffering from this syndrome is about 30 years.

MODY 4 is a form of maturity onset diabetes of the young.

MODY 4 arises from mutations of the PDX1 homeobox gene on chromosome 13. Pdx-1 is a transcription factor vital to the development of the embryonic pancreas. Even in adults it continues to play a role in the regulation and expression of genes for insulin, GLUT2, glucokinase, and somatostatin.

MODY 4 is so rare that only a single family has been well-studied. A child born with pancreatic agenesis (absence of the pancreas) was found to be homozygous for Pdx-1 mutations. A number of older relatives who were heterozygous had mild hyperglycemia or diabetes. None were severely insulin-deficient and all were controlled with either diet or oral hypoglycemic agents.

No major organization recommends universal screening for diabetes as there is no evidence that such a program improve outcomes. Screening is recommended by the United States Preventive Services Task Force (USPSTF) in adults without symptoms whose blood pressure is greater than 135/80 mmHg. For those whose blood pressure is less, the evidence is insufficient to recommend for or against screening. There is no evidence that it changes the risk of death in this group of people. They also recommend screening among those who are overweight and between the ages of 40 and 70.

The World Health Organization recommends testing those groups at high risk and in 2014 the USPSTF is considering a similar recommendation. High-risk groups in the United States include: those over 45 years old; those with a first degree relative with diabetes; some ethnic groups, including Hispanics, African-Americans, and Native-Americans; a history of gestational diabetes; polycystic ovary syndrome; excess weight; and conditions associated with metabolic syndrome. The American Diabetes Association recommends screening those who have a BMI over 25 (in people of Asian descent screening is recommended for a BMI over 23).

Turner syndrome may be diagnosed by amniocentesis or chorionic villus sampling during pregnancy.

Usually, fetuses with Turner syndrome can be identified by abnormal ultrasound findings ("i.e.", heart defect, kidney abnormality, cystic hygroma, ascites). In a study of 19 European registries, 67.2% of prenatally diagnosed cases of Turner Syndrome were detected by abnormalities on ultrasound. 69.1% of cases had one anomaly present, and 30.9% had two or more anomalies.

An increased risk of Turner syndrome may also be indicated by abnormal triple or quadruple maternal serum screen. The fetuses diagnosed through positive maternal serum screening are more often found to

have a mosaic karyotype than those diagnosed based on ultrasonographic abnormalities, and

conversely, those with mosaic karyotypes are less likely to have associated ultrasound abnormalities.

Acanthosis nigricans should be distinguished from the casal collar appearing in pellagra.

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

Treatment is depended on the type of glycogen storage disease. E.g. GSD I is typically treated with frequent small meals of carbohydrates and cornstarch to prevent low blood sugar, while other treatments may include allopurinol and human granulocyte colony stimulating factor.

Turner syndrome can be diagnosed postnatally at any age. Often, it is diagnosed at birth due to heart problems, an unusually wide neck or swelling of the hands and feet. However, it is also common for it to go undiagnosed for several years, typically until the girl reaches the age of puberty/adolescence and she fails to develop properly (the changes associated with puberty do not occur). In childhood, a short stature can be indicative of Turner syndrome.

A test called a karyotype, also known as a chromosome analysis, analyzes the chromosomal composition of the individual. This is the test of choice to diagnose Turner syndrome.

Acanthosis nigricans is typically diagnosed clinically. A skin biopsy may be needed in unusual cases. If no clear cause is obvious, it may be necessary to search for one. Blood tests, an endoscopy, or X-rays may be required to eliminate the possibility of diabetes or cancer as the cause.

On biopsy, hyperkeratosis, epidermal folding, leukocyte infltration, and melanocyte proliferation may be seen.

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.

Diagnosis requires a neurological examination and neuroimaging can be helpful.

BVVL can be differentially diagnosed from similar conditions like Fazio-Londe syndrome and amyotrophic lateral sclerosis, in that those two conditions don't involve sensorineural hearing loss, while BVVL, Madras motor neuron disease, Nathalie syndrome, and Boltshauser syndrome do. Nathalie syndrome does not involve lower cranial nerve symptoms, so it can be excluded if those are present. If there is evidence of lower motor neuron involvement, Boltshauser syndrome can be excluded. Finally, if there is a family history of the condition, then BVVL is more likely than MMND, as MMND tends to be sporadic.

Genetic testing is able to identify genetic mutations underying BVVL.

A cure for Werner syndrome has not yet been discovered. It is often treated by managing the associated diseases and relieving symptoms to improve quality of life. The skin ulcers that accompany WS can be treated in several ways, depending on the severity. Topical treatments can be used for minor ulcers, but are not effective in preventing new ulcers from occurring. In the most severe cases, surgery may be required to implant a skin graft or amputate a limb if necessary. Diseases commonly associated with Werner Syndrome such as diabetes and cancer are treated in generally the same ways as they would be for a non-Werner Syndrome individual. A change in diet & exercise can help prevent and control arteriosclerosis, and regular cancer screenings can allow for early detection of cancer.

There is recent evidence that suggests that the cytokine-suppressive anti-inflammatory drug, SB203580, may be a possible therapeutic option for patients with Werner's Syndrome. This drug targets the p38 signaling pathway, which may become activated as a result of genomic instability and stalled replication forks that are characteristic mutations in WS. This activation of p38 may play a role in the onset of premature cell aging, skin aging, cataracts, and graying of the hair. The p38 pathway has also been implicated in the anti-inflammatory response that causes atherosclerosis, diabetes, and osteoporosis, all of which are associated with Werner's Syndrome. This drug has shown to revert the aged characteristics of young WS cells to those seen in normal, young cells and improve the lifespan of WS cells "in vitro". SB203580 is still in the clinical trial stages, and the same results have not yet been seen "in vivo".

In 2010, vitamin C supplementation was found to reverse the premature aging and several tissue dysfunctions in a genetically modified mouse model of the disease. Vitamin C supplementation also appeared to normalize several age-related molecular markers such as the increased levels of the transcription factor NF-κB. In addition, it decreases activity of genes activated in human Werner syndrome and increases gene activity involved in tissue repair. Supplementation of vitamin C is suspected to be beneficial in the treatment of human Werner syndrome, although there was no evidence of anti-aging activity in nonmutant mice. In general, treatments are available for only the symptoms or complications and not for the disease itself.

Diabetes mellitus may be effectively managed by appropriate meal planning, increased physical activity and properly-instituted insulin treatment. Some tips for controlling diabetes in pregnancy include:

- Meals – Cut down sweets, eats three small meals and one to three snacks a day, maintain proper mealtimes, and include balanced fiber intake in the form of fruits, vegetables and whole-grains.

- Increased physical activity - walking, swimming/aquaerobics, etc.

- Monitor blood sugar level frequently, doctors may ask to check the blood glucose more often than usual.

- The blood sugar level should be below 95 mg/dl (5.3 mmol/l) on awakening, below 140 mg/dl (7.8 mmol/l) one hour after a meal and below 120 mg/dl (6.7 mmol/l) two hours after a meal.

- Each time when checking the blood sugar level, keep a proper record of the results and present to the health care team for evaluation and modification of the treatment. If blood sugar levels are above targets, a perinatal diabetes management team may suggest ways to achieve targets.

- Many may need extra insulin during pregnancy to reach their blood sugar target. Insulin is not harmful for the baby.