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.

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.

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.

Malpuech syndrome has been shown to have physical, or phenotypical similarities with several other genetic disorders. A report by Reardon et al. (2001) of a nine-year-old boy exhibiting facial, caudal and urogenital anomalies consistent with Malpuech syndrome, who also had skeletal malformites indicative of Juberg-Hayward syndrome, suggests that the two disorders may be allelic (caused by different mutations of the same gene).

Along with several other disorders that have similar, or overlapping features and autosomal recessive inheritance, Malpuech syndrome has been considered to belong under the designation "3MC syndrome". Titomanlio et al. (2005) described a three-year-old female known to have Michels syndrome. In their review of the physical similarities between Michels, Malpuech and Mingarelli-Carnevale syndromes—particularly the facial appearance including instances of cleft lip and palate, and ptosis, and a similarity of congenital abdominal and urogenital anomalies—they believed the syndromes may represent a spectrum of genetic disorders rather than three individual disorders. They initially suggested this spectrum could be named 3MC (Michels-Malpuech-Mingarelli-Carnevale) syndrome. This conclusion and the name 3MC syndrome was supported by Leal et al. (2008), who reported a brother and sister with an array of symptoms that overlapped the various syndromes. Further assertion of 3MC syndrome was by Rooryck et al. (2011) in an elaboration of its cause.

The brain is usually grossly abnormal in outline when someone is diagnosed with Miller–Dieker syndrome. Only a few shallow sulci and shallow Sylvian fissures are seen; this takes on an hourglass or figure-8 appearance on the axial imaging. The thickness and measurement for a person without MDS is 3–4 mm. With MDS, a person's cortex is measured at 12–20 mm.

While no cure for MDS is available yet, many complications associated with this condition can be treated, and a great deal can be done to support or compensate for functional disabilities. Because of the diversity of the symptoms, it can be necessary to see a number of different specialists and undergo various examinations, including:

- Developmental evaluation

- Cardiologists evaluation

- Otolaryngology

- Treatment of seizures

- Urologic evaluation

- Genetic counseling-balanced chromosomal translocation should be excluded in a parents with an affected child are planning another pregnancy, so parents with affected children should visit a genetic counselor.

Diagnosis of otodental syndrome was established using clinical, histopathological and audiometric methodologies. In normal individuals, by the age of 2-3, radiograph images should depict any signs of premolar development. A formal diagnosis of no premolar growth can be done by age 6 in order to check for signs of otodental syndrome. Sensorineural hearing loss can be another measure for proper diagnosis as well as checking for ocular coloboma. The latter is usually noticed at an around birth.

Molecular genetic testing can aid in the diagnosis of the affected individual, which would determine if there are any abnormalities in the FGF3 gene (11q13) or the FADD gene (11q13.3). Additional tests that can help diagnose otodental syndrome are ear infection tests, hearing tests, oral examination, and eye examinations to check for the specific phenotypic associations. Due to the rarity of otodental syndrome, most symptoms are looked at on an individual basis unless multiple symptoms are all apparent at once.

There is potential for differential diagnosis due to similarities in symptoms. Other diseases that share common symptoms are chondroectodermal dysplasia, achondrodysplasia, and osteopetrosis

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.

Currently there are no open research studies for otodental syndrome. Due to the rarity of this disease, current research is very limited.

The most recent research has involved case studies of the affected individuals and/or families, all of which show the specific phenotypic symptoms of otodental syndrome. Investigations on the effects of FGF3 and FADD have also been performed. These studies have shown successes in supporting previous studies that mutations to FGF3 and neighboring genes may cause the associated phenotypic abnormalities. According to recent studies involving zebrafish embryos, there is also support in that the FADD gene contributed to ocular coloboma symptoms as well.

Future research studies are required in order to better grasp the specific relationship between the gene involved and its effect on various tissues and organs such as teeth, eyes, and ear. Little is known and there is still much to be determined.

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.

Microlissencephaly can be diagnosed by prenatal MRI. MRI is better than ultrasound when it comes to detecting microlissencephaly or MSGP prenatally.

The ideal time for proper prenatal diagnosis is between the 34th and 35th gestational week which is the time when the secondary gyration normally terminates. In microlissencephaly cases, the primary sulci would be unusually wide and flat while secondary sulci would be missing.

At birth, lissencephaly with a head circumference of less than minus three standard deviations (< –3 SD) is considered microlissencephaly.

Although genetic diagnosis in patients with MLIS is challenging, exome sequencing has been suggested to be a powerful diagnostic tool.

Syndactyly and other deformities are typically observed and diagnosed at birth. Long QT syndrome sometimes presents itself as a complication due to surgery to correct syndactyly. Other times, children collapse spontaneously while playing. In all cases it is confirmed with ECG measurements. Sequencing of the CACNA1C gene further confirms the diagnosis.

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).

Treatment of 3-M syndrome is aimed at the specific symptoms presented in each individual. With the various symptoms of this disorder being properly managed and affected individuals having normal mental development, 3-M syndrome is not a life - threatening condition and individuals are able to lead a near normal life with normal life expectancy.

Treatment may involve the coordinated efforts of many healthcare professionals, such as pediatricians, orthopedists, dentists and/or other specialists depending on the symptoms.

- Possible management options for short stature are surgical bone lengthening or growth hormone therapy.

- Orthopedic techniques and surgery may be used to treat certain skeletal abnormalities.

- Plastic surgery may also be performed on individuals to help correct certain cranio-facial anomalies.

- Individuals with dental abnormalities may undergo corrective procedures such as braces or oral surgeries.

Recent research has been focused on studying large series of cases of 3-M syndrome to allow scientists to obtain more information behind the genes involved in the development of this disorder. Knowing more about the underlying mechanism can reveal new possibilities for treatment and prevention of genetic disorders like 3-M syndrome.

- One study looks at 33 cases of 3M syndrome, 23 of these cases were identified as CUL7 mutations: 12 being homozygotes and 11 being heterozygotes. This new research shows genetic heterogeneity in 3M syndrome, in contrast to the clinical homogeneity. Additional studies are still ongoing and will lead to the understanding of this new information.

- This study provides more insight on the three genes involved in 3M syndrome and how they interact with each other in normal development. It lead to the discovery that the CUL7, OBS1, and CCDC8 form a complex that functions to maintain microtubule and genomic integrity.

Microlissencephaly is considered a more severe form than microcephaly with simplified gyral pattern. Microlissencephaly is characterized by a smooth cortical surface (absent sulci and gyri) with a thickened cortex (> 3 mm) and is usually associated with other congenital anomalies. Microcephaly with a simplified gyral pattern has too few sulci and normal cortical thickness (3 mm) and is usually an isolated anomaly.

In a sample of 19 children, a 1997 study found that 3 died before the age of 3, and 2 never learned to walk. The children had various levels of delayed development with developmental quotients from 60 to 85.

Prevalence ranges from 1 in 3500 to 5600 live births. Male-female ratio is found to be 3:2.

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.

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 a newborn boy thought to have Fryns syndrome, Clark and Fenner-Gonzales (1989) found mosaicism for a tandem duplication of 1q24-q31.2. They suggested that the gene for this disorder is located in that region. However, de Jong et al. (1989), Krassikoff and Sekhon (1990), and Dean et al. (1991) found possible Fryns syndrome associated with anomalies of chromosome 15, chromosome 6, chromosome 8(human)and chromosome 22, respectively. Thus, these cases may all represent mimics of the mendelian syndrome and have no significance as to the location of the gene for the recessive disorder.

By array CGH, Slavotinek et al. (2005) screened patients with DIH and additional phenotypic anomalies consistent with Fryns syndrome for cryptic chromosomal aberrations. They identified submicroscopic chromosome deletions in 3 probands who had previously been diagnosed with Fryns syndrome and had normal karyotyping with G-banded chromosome analysis. Two female infants were found to have microdeletions involving 15q26.2 (see 142340), and 1 male infant had a deletion in band 8p23.1 (see 222400).

The prognosis for patients diagnosed with Timothy syndrome is very poor. Of 17 children analyzed in one study, 10 died at an average age of 2.5 years. Of those that did survive, 3 were diagnosed with autism, one with an autism spectrum disorder, and the last had severe delays in language development. One patient with atypical Timothy syndrome was largely normal with the exception of heart arrhythmia. Likewise, the mother of two Timothy syndrome patients also carried the mutation but lacked any obvious phenotype. In both of these cases, however, the lack of severity of the disorder was due to mosaicism.

The disorder is characterized by absence or underdevelopment of the cerebellar vermis and a malformed brain stem (molar tooth sign), both of which can be visualized on a MRI scan. Together with this sign, the diagnosis is based on the physical symptoms and genetic testing for mutations. If the gene mutations have been identified in a family member, prenatal or carrier diagnosis can be pursued.

Joubert Syndrome is known to affect 1 in 80,000-100,000 newborns. Due to the variety of genes this disorder is affected by, it is likely to be under-diagnosed. It is commonly found in Ashkenazi Jewish, French-Canadians, and Hutterite ethnic populations. Most cases of Joubert syndrome are autosomal recessive - in these cases, both parents are either carriers or affected. Rarely, Joubert syndrome is inherited in an X-linked recessive pattern. In these cases, males are more commonly affected because affected males must have one X chromosome mutated, while affected females must have mutated genes on both X chromosomes.

During pregnancy, even in the absence of preconception cardiovascular abnormality, women with Marfan syndrome are at significant risk of aortic dissection, which is often fatal even when rapidly treated. Women with Marfan syndrome, then, should receive a thorough assessment prior to conception, and echocardiography should be performed every six to 10 weeks during pregnancy, to assess the aortic root diameter. For most women, safe vaginal delivery is possible.

Marfan syndrome is expressed dominantly. This means a child with one parent a bearer of the gene has a 50% probability of getting the syndrome. In 1996, the first preimplantation genetic testing (PGT) therapy for Marfan was conducted; in essence PGT means conducting a genetic test on early-stage IVF embryo cells and discarding those embryos affected by the Marfan mutation.

Heart-hand syndrome type 2 is also known as Berk–Tabatznik syndrome. Berk–Tabatznik syndrome is a condition with an unknown cause that shows symptoms of short stature, congenital optic atrophy and brachytelephalangy. This condition is extremely rare with only two cases being found.