In terms of genetic testing, while it is done for "type 1" of this condition, "type 2" will only render (or identify) those genes which place the individual at higher risk. Other methods/exam to ascertain if an individual has autoimmune polyendocrine syndrome type 2 are:

- CT scan

- MRI

- Ultrasound

The diagnosis is usually based on clinical features present at birth.

Ultrasound in the second trimester may show abnormalities associates with NLS, including polyhydramnios, intrauterine growth restriction, microcephaly, proptosis and decreased fetal motility.

The prognosis is poor; affected individuals are either stillborn or die shortly after birth. The longest survival reported in literature is of 134 days.

This syndrome is transmitted as an autosomal recessive disorder and there is a risk for recurrence of 25% in future pregnancies.

1. Clinical Genetics and Genetic Testing

Genetic testing is necessary to confirm the diagnosis of PMS. A prototypical terminal deletion of 22q13 can be uncovered by karyotype analysis, but many terminal and interstitial deletions are too small to detect with this method. Chromosomal microarray should be ordered in children with suspected developmental delays or ASD. Most cases will be identified by microarray; however, small variations in genes might be missed. The falling cost for whole exome sequencing may replace DNA microarray technology for candidate gene evaluation. Biological parents should be tested with fluorescence "in situ" hybridization (FISH) to rule out balanced translocations or inversions. Balanced translocation in a parent increases the risk for recurrence and heritability within families (figure 3).

Clinical genetic evaluations and dysmorphology exams should be done to evaluate growth, pubertal development, dysmorphic features (table 1) and screen for organ defects (table 2)

2. Cognitive and Behavioral Assessment

All patients should undergo comprehensive developmental, cognitive and behavioral assessments by clinicians with experience in developmental disorders. Cognitive evaluation should be tailored for individuals with significant language and developmental delays. All patients should be referred for specialized speech/language, occupational and physical therapy evaluations.

3. Neurological Management

Individuals with PMS should be followed by a pediatric neurologist regularly to monitor motor development, coordination and gait, as well as conditions that might be associated with hypotonia. Head circumference should be performed routinely up until 36 months. Given the high rate of seizure disorders (up to 41% of patients) reported in the literature in patients with PMS and its overall negative impact on development, an overnight video EEG should be considered early to rule out seizure activity. In addition, a baseline structural brain MRI should be considered to rule out the presence of structural abnormalities.

4. Nephrology

All patients should have a baseline renal and bladder ultrasonography and a voiding cystourethrogram should be considered to rule out structural and functional abnormalities. Renal abnormalities are reported in up to 38% of patients with PMS. Vesicouretral reflux, hydronephrosis, renal agenesis, dysplasic kidney, polycystic kidney and recurrent urinary tract infections have all been reported in patients with PMS.

5. Cardiology

Congenital heart defects (CHD) are reported in samples of children with PMS with varying frequency (up to 25%)(29,36). The most common CHD include tricuspid valve regurgitation, atrial septal defects and patent ductus arteriousus. Cardiac evaluation, including echocardiography and electrocardiogram, should be considered.

6. Gastroenterology

Gastrointestinal symptoms are common in individuals with PMS. Gastroesophageal reflux, constipation, diarrhea and cyclic vomiting are frequently described.

Table 3: Clinical Assessment Recommendations in Phelan McDermid Syndrome.

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.

Management of autoimmune polyendocrine syndrome type 2 consists of the following:

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.

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.

In order to ascertain if an individual has activated PI3K delta syndrome, usually one finds atypical levels of immunoglobulins. Methods to determine the condition are the following:

- Genetic testing

- Laboratory findings

- Symptoms exhibited

The diagnosis of Perlman syndrome is based on observed phenotypic features and confirmed by histological examination of the kidneys. Prenatal diagnosis is possible for families that have a genetic disposition for Perlman syndrome although there is no conclusive laboratory test to confirm the diagnosis. Fetal overgrowth, particularly with an occipitofrontal circumference (OFC) greater than the 90th centile for gestational age, as well as an excess of amniotic fluid in the amniotic sac (polyhydramnios), may be the first signs of Perlman. Using ultrasound diagnosis, Perlman syndrome has been detected at 18 weeks. During the first trimester, the common abnormalities of the syndrome observed by ultrasound include cystic hygroma and a thickened nuchal lucency. Common findings for the second and third trimesters include macrosomia, enlarged kidneys, renal tumors (both hamartoma and Wilms), cardiac abnormalities and visceromegaly.

Prompt recognition and identification of the disorder along with accurate follow-up and clinical assistance is recommended as the prognosis for Perlman is severe and associated with a high neonatal death rate.

In 1989, diagnostic criteria was created for the diagnosing of Winchester syndrome. The typical diagnosis criteria begin with skeletal radiological test results and two of the defining symptoms, such as short stature, coarse facial features, hyperpigmentation, or excessive hair growth. The typical tests that are performed are x-ray and magnetic resonance imaging. It appears that Winchester syndrome is more common in women than men. Winchester syndrome is very rare. There have only been a few individuals worldwide who were reported to have this disorder.

With appropriate treatment and management, patients with Weaver syndrome appear to do well, both physically and intellectually, throughout their life and have a normal lifespan. Their adult height is normal as well.

There is no cure available for Weaver syndrome. However, with multidisciplinary management such as neurological, pediatric, orthopedic, and psychomotor care and genetic counseling, symptoms can be managed. Surgery may be used to correct any skeletal issues. Physical and occupational therapy are considered an option to help with muscle tone. Also, speech therapy is often recommended for speech related problems.

Perlman syndrome shares clinical overlaps with other overgrowth disorders, with similarities to Beckwith–Wiedemann syndrome and Simpson-Golabi-Behmel syndrome having been particularly emphasized in scientific study. Similarities with Beckwith-Wiedemann syndrome include polyhydramnios, macrosomia, nephromegaly and hypoglycaemia. It is the distinctive facial dysmorphology of Perlman, including deep-set eyes, depressed nasal bridge, everted upper lip, and macrocephaly which allows the two conditions to be distinguished from one another. Diagnosis of Perlman syndrome also overlaps with other disorders associated with Wilms tumor, namely, Sotos syndrome and Weaver syndrome.

The key problem is the early fusion of the skull, which can be corrected by a series of surgical procedures, often within the first three months after birth. Later surgeries are necessary to correct respiratory and facial deformities.

Some suggestions for surveillance for cancer include the following:

- Small intestine with small bowel radiography every 2 years,

- Esophagogastroduodenoscopy and colonoscopy every 2 years,

- CT scan or MRI of the pancreas yearly,

- Ultrasound of the pelvis (women) and testes (men) yearly,

- Mammography (women) from age 25 annually livelong, and

- Papanicolaou smear (Pap smear) every year

Follow-up care should be supervised by a physician familiar with Peutz–Jeghers syndrome. Genetic consultation and counseling as well as urological and gynecological consultations are often needed.

There is no known cure for Winchester syndrome; however, there are many therapies that can aid in the treatment of symptoms. Such treatments can include medications: anti-inflammatories, muscle relaxants, and antibiotics. Many individuals will require physical therapy to promote movement and use of the limbs affected by the syndrome. Genetic counseling is typically prescribed for families to help aid in the understanding of the disease. There are a few clinical trials available to participate in. The prognosis for patients diagnosed with Winchester syndrome is positive. It has been reported that several affected individuals have lived to middle age; however,the disease is progressive and mobility will become limited towards the end of life. Eventually, the contractures will remain even with medical intervention, such as surgery.

Children with Pfeiffer syndrome types 2 and 3 "have a higher risk for neurodevelopmental disorders and a reduced life expectancy" than children with Pfeiffer syndrome type 1, but if treated, favorable outcomes are possible. In severe cases, respiratory and neurological complications often lead to early death.

In terms of the treatment for ativated PI3K delta syndrome, generally primary immunodeficiencies see the following used:

- Bacterial infection should be treated rapidly(with antibiotics)

- Antiviral therapy

- Modify lifestyle(exposure to pathogens need to be minimized)

Treatment is usually confined to such surgical intervention as may be necessary to help the child to develop e.g. jaw distraction/bone grafts, ocular dermoid debulking (see below), repairing cleft palate/lip, repairing heart malformations or spinal surgery. Some patients with Goldenhar syndrome will require assistance as they grow by means of hearing aids or glasses.

Stem cell grafting (womb tissue grafting) has been successfully used to "reprogram" eye dermoids, effectively halting the regrowth of eye dermoids.

These tissues that grow on the eye are "mis-programmed" cells (sometimes tooth or nail cells instead of eye cells).

There is currently no cure for GAPO syndrome, but some options are available to reduce the symptoms. Nearsightedness, which affects some sufferers of the disease, can be treated by corrective lenses. Unfortunately, optic atrophy as a result of degradation of the optic nerve (common with GAPO syndrome) cannot be corrected. Corticosteroids have been proposed as a treatment for optic nerve atrophy, but their effectiveness is disputed, and no steroid based treatments are currently available.

The true prevalence of PMS has not been determined. More than 1200 people have been identified worldwide according the Phelan-McDermid Syndrome Foundation. However, it is believed to be underdiagnosed due to inadequate genetic testing and lack of specific clinical features. It is known to occur with equal frequency in males and females. Studies using chromosomal microarray for diagnosis indicate that at least 0.5% of cases of ASD can be explained by mutations or deletions in the "SHANK3" gene. In addition when ASD is associated with ID, "SHANK3" mutations or deletions have been found in up to 2% of individuals.

The incidence of Fraser syndrome is 0.043 per 10,000 live born infants and 1.1 in 10,000 stillbirths, making it a rare syndrome.

Medical diagnosis of CGL can be made after observing the physical symptoms of the disease: lipoatrophy (loss of fat tissues) affecting the trunk, limbs, and face; hepatomegaly; acromegaly; insulin resistance; and high serum levels of triglycerides. Genetic testing can also confirm the disease, as mutations in the AGPAT2 gene is indicative of CGL1, a mutation in the BSCL2 gene is indicative of CGL2, and mutations in the CAV1 and PTRF genes are indicative of CGL3 and CGL4 respectively. Physical diagnosis of CGL is easier, as CGL patients are recognizable from birth, due to their extreme muscular appearance, which is caused by the absence of subcutaneous fat.

CGL3 patients have serum creatine kinase concentrations much higher than normal (2.5 to 10 times the normal limit). This can be used to diagnose type 3 patients and differentiate them from CGL 1 and 2 without mapping their genes. Additionally, CGL3 patients have low muscle tone when compared with other CGL patients.

Diagnosis of Bruck syndrome must distinguish the association of contractures and skeletal fragility. Ultrasound is used for prenatal diagnosis. The diagnosis of a neonate bears resemblance to arthrogryposis multiplex congenital, and later in childhood to osteogenesis imperfecta.