Physical Symptoms

- Heart Defects

- Characteristics of Autism

- Genital defects (in males)

- Childhood hypotonia

- Respiratory infections

- Motor Delay

- Renal defects

Behavioural Symptoms

- Passiveness

- Sociability

- Aggression

- Biting, and/or hitting

- Moodiness

- Disliking routine changes

Recognised symptoms up till now are:

- Autism or autistic behaviors

- ADHD

- Learning disability

- Large head

- Dysmorphic facial appearance - mild

- Prominent forehead

- Wide-set eyes (hypertelorism)

- Schizophrenia

- Loose joints

- GERD

- Sleep disturbances

- Sleep Apnea

- Underdeveloped parts of brain - corpus callosum and cerebellar vermis

- Neuroblastoma

- Speech & developmental delays

- Chiari malformation of the brain

- Congenital heart defects

- Hypotonia

It is not clear whether the list of symptoms is complete. Very little information is known about the syndrome. The symptomology may be different among individuals, even in the same family.

Affected individuals present with a broad array of medical and behavioral manifestations (tables 1 and 2). Patients are consistently characterized by global developmental delay, intellectual disability, speech abnormalities, ASD-like behaviors, hypotonia and mild dysmorphic features. Table 1 summarizes the dysmorphic and medical conditions that have been reported in individuals with PMS. Table 2 summarize the psychiatric and neurological associated with PMS. Most of the studies include small samples or relied on parental report or medical record review to collect information, which can account in part for the variability in the presentation of some of the presenting features. Larger prospective studies are needed to further characterize the phenotype.

Table 1: Dysmorphic features and medical comorbid conditions that have been reported in individuals with Phelan McDermid Syndrome.

Table 2: Psychiatric and Neurologic Manifestations associated with Phelan McDermid Syndrome

The most common symptoms are intellectual disability and recurrent seizures developing in infancy or early childhood. Typically the seizures are resistant to treatment with anti-epileptic drugs. Other symptoms may include:

- Microcephaly

- Lymphedema

- Facial abnormalities

- Immune deficiencies

- Abnormalities of retina

- Slow growth

- Short stature

1q21.1 duplication syndrome or 1q21.1 (recurrent) microduplication is a rare aberration of chromosome 1.

In a common situation a human cell has one pair of identical chromosomes on chromosome 1. With the 1q21.1 duplication syndrome one chromosome of the pair is over complete, because a part of the sequence of the chromosome is duplicated twice or more. In 1q21.1, the '1' stands for chromosome 1, the 'q' stands for the long arm of the chromosome and '21.1' stands for the part of the long arm in which the duplication is situated.

Next to the duplication syndrome, there is also a 1q21.1 deletion syndrome. While there are two or three copies of a similar part of the DNA on a particular spot with the duplication syndrome, there is a part of the DNA missing with the deletion syndrome on the same spot. Literature refers to both the deletion and the duplication as the 1q21.1 copy-number variations (CNV).

The CNV leads to a very variable phenotype and the manifestations in individuals are quite variable. Some people who have the syndrome can function in a normal way, while others have symptoms of mental retardation and various physical anomalies.

EEM syndrome exhibits a combination of prominent symptoms and features. These include: ectodermal dysplasia (systemic malformations of ectodermal tissues), ectrodactyly ("lobster claw" deformity in the hands and feet), macular dystrophy (a progressive eye disease), syndactyly (webbed fingers or toes), hypotrichosis (a type of hair-loss), and dental abnormalities (hypodontia).

22q13 deletion syndrome (spoken as "twenty-two q one three", see Locus (genetics)) is a genetic disorder caused by deletions or rearrangements on the q terminal end (long arm) of chromosome 22. Any abnormal genetic variation in the q13 region that presents with significant manifestations (phenotype) typical of a terminal deletion may be diagnosed as 22q13 deletion syndrome. 22q13 deletion syndrome is often called Phelan-McDermid syndrome (abbreviated PMS). There is disagreement among researchers as to the exact definition of 22q13 deletion syndrome. The Developmental Synaptopathies Consortium defines PMS as being caused by "SHANK3" mutations, a definition that appears to exclude terminal deletions. The requirement to include "SHANK3" in the definition is supported by many, but not by those who first described 22q13 deletion syndrome.

A prototypical terminal deletion of 22q13 can be uncovered by karyotype analysis, but many terminal and interstitial deletions are too small. The availability of DNA microarray technology for revealing multiple genetic problems simultaneously has been the diagnostic tool of choice. The falling cost for whole exome sequencing and, eventually, whole genome sequencing, may replace DNA microarray technology for candidate evaluation. However, fluorescence in situ hybridization (FISH) tests remain valuable for diagnosing cases of mosaicism (mosaic genetics) and chromosomal rearrangements (e.g., ring chromosome, unbalanced chromosomal translocation). Although early researchers sought a monogenic (single gene genetic disorder) explanation, recent studies have not supported that hypothesis (see Etiology, below).

Proteus syndrome causes an overgrowth of skin, bones, muscles, fatty tissues, and blood and lymphatic vessels.

Proteus syndrome is a progressive condition wherein children are usually born without any obvious deformities. Tumors of skin and bone growths appear as they age typically in early childhood. The musculoskeletal manifestations are cardinal for the diagnosis of Proteus syndrome. The severity and locations of these various asymmetrical growths vary greatly but typically the skull, one or more limbs, and soles of the feet will be affected. There is a risk of premature death in affected individuals due to deep vein thrombosis and pulmonary embolism caused by the vessel malformations that are associated with this disorder. Because of carrying excess weight and enlarged limbs, arthritis and muscle pain may also be symptoms — as is the case for Mandy Sellars, a woman who has been diagnosed with a form of Proteus syndrome (but see "Notable Cases" below). Further risks may occur due to the mass of extra tissue.

The disorder itself does not uniformly cause learning impairments: the distribution of intelligence deficits among sufferers of Proteus syndrome appears higher than that of the general population, although this is difficult to determine with statistical significance. In addition, the presence of visible deformity may have a negative effect on the social experiences of the sufferer, causing cognitive and social deficits.

Afflicted individuals are at increased risk for developing certain tumors including unilateral Ovarian cystadenomas, testicular tumors, meningiomas, and monomorphic adenomas of the parotid gland.

Hemimegalencephaly is often found to be associated.

The musculoskeletal manifestations of Proteus syndrome are frequent and recognizable. Patients tend to demonstrate a unique pattern of skeletal abnormalities. The orthopaedic features are usually bilateral, asymmetrical, progressive and involving all four limbs and spine. Afflicted patients usually have localized periarticular limb distortions, limb length discrepancy, and spine deformity. Patients with Proteus syndrome can have regular bone configuration and contours despite the bone enlargement. Patients can also exhibit hyperthyroidism of the skull and facial abnormalities. Because of the rarity of the syndrome and the variability of signs, the orthopaedic management should be individualized.

Ring chromosome 14 syndrome is a very rare human chromosome abnormality. It occurs when one or both of the telomeres that mark the ends of chromosome 14 are lost allowing the now uncapped ends to fuse together forming a ring chromosome. It causes a number of serious health issues.

ATR-16 syndrome affects the blood, development, and brain; symptoms vary based on the specific genes deleted on chromosome 16. Because it is so rare, it is difficult to determine the "core" symptoms of the disease. People with ATR-16 have alpha-thalassemia, a blood disorder where there is less normal hemoglobin in the blood than there should be, and the red blood cells are smaller than they should be (microcytic anemia). Affected children have various characteristic physical features, including clubfoot, "locked" little fingers, microcephaly (small head), hypertelorism (widely spaced eyes), broad, prominent nose bridge, downward-slanted palpebral fissures, small ears, retrognathia, and short neck. Children with ATR-16 syndrome also have mild to moderate intellectual disabilities, developmental delays/growth delays, and speech delays. Some children with ATR-16 have seizures, cryptorchidism (undescended testes), or hypospadias.

A ring chromosome is an aberrant chromosome whose ends have fused together to form a ring. Ring chromosomes were first discovered by Lilian Vaughan Morgan in 1926. A ring chromosome is denoted by the symbol "r" in human genetics and "R" in Drosophila genetics. Ring chromosomes may form in cells following genetic damage by mutagens like radiation, but they may also arise spontaneously during development.

The brain is abnormally smooth, with fewer folds and grooves. The face, especially in children, has distinct characteristics including a short nose with upturned nares, thickened upper lip with a thin vermilion upper border, frontal bossing, small jaw, low-set posteriorily rotated ears, sunken appearance in the middle of the face, widely spaced eyes, and hypertelorism. The forehead is prominent with bitemporal hollowing.

Characteristics that are not visual include mental retardation, pre- and postnatal growth retardation, epilepsy, and reduced lifespan.

Failure to thrive, feeding difficulties, seizures and decreased spontaneous activity are often seen. Death usually occurs in infancy and childhood.

Multiple abnormalities of the brain, kidneys, and gastrointestinal tract (the stomach and intestines) may occur.

Ring 18 causes a wide range of medical and developmental concerns. As discussed above, people with ring 18 can have features of both distal 18q- and 18p-. The features of distal 18q- and 18p- vary greatly because of the variability of the deletion size and breakpoint locations between people. Because ring 18 can involve unique deletions of both the p and q arms of the chromosome there is twice as much reason for the variability between individuals. This variation is also partly attributable to the incidence of mosaicism, which is relatively common in people with ring 18.

- Holoprosencephaly has been reported in some people with ring 18. This is due to the deletion of the TGIF gene on the short arm of chromosome 18 in some people with ring 18.Approximately 30-40% of people with ring 18 have a congenital heart anomaly. Septal defects are the most common type of defect reported in this population.

- Hypotonia is frequently seen in the ring 18 population. Seizures, though uncommon, have been reported in people with ring 18.

- In some children without “classic” holoprosencephaly, microforms of holoprosencephaly may be noted on MRI, including missing olfactory tracts and bulbs and absent or hypoplastic corpus callosum.

- Strabismus as well as nystagmus have both been reported in infants and children with ring 18.

- Hearing loss has been reported and may be related to ear canal atresia or stenosis.

- Umbilical and inguinal hernias have been reported in a small number of people with ring 18.

- Unilateral renal hypoplasia and aplasia have both been reported in individuals with ring 18. Hydronephrosis as well as pyelonephritis have also been reported in a few individuals. Cryptorchidism, hypospadias, and micropenis have been seen in males with ring 18, while females have been reported with hypoplastic labia.

- Foot abnormalities are common within the ring 18 population. Scoliosis as well as pectus excavatum have also been frequently reported.

- Several people with ring 18 have growth hormone deficiency. Hypothyroidism has also been reported in a minority of people.

- Cognitive ability varies; according to a literature review, the degree of impairment may fall anywhere between the mild and severe ends of the spectrum.

- Facial features of ring 18 include low-set, dysplastic ears, epicanthic folds, and hypertelorism. Micrognathia has also been reported.

Ring 18 is a genetic condition caused by a deletion of the two tips of chromosome 18 followed by the formation of a ring-shaped chromosome. It was first reported in 1964.

Individuals affected by AAA have adrenal insufficiency/Addison's disease due to ACTH resistance, alacrima (absence of tear secretion), and achalasia (a failure of a ring of muscle fibers, such as a sphincter, to relax) of the lower esophageal sphincter at the cardia which delays food going to the stomach and causes dilation of the thoracic esophagus. There may also be signs of autonomic dysfunction with AAA, such as pupillary abnormalities, an abnormal reaction to intradermal histamine, abnormal sweating, orthostatic hypotension, and disturbances of the heart rate. Hypoglycemia (low blood sugar) is often mentioned as an early sign. The disorder has also been associated with mild mental retardation.

The syndrome is highly variable. Managed effectively, affected individuals can have a normal lifespan and bear children.

9q34 deletion syndrome, also known as Kleefstra syndrome, is a rare genetic disorder. Terminal deletions of chromosome 9q34 have been associated with childhood hypotonia, a distinctive facial appearance and developmental disability. The facial features typically described include arched eyebrows, small head circumference, midface hypoplasia, prominent jaw and a pouting lower lip. Individuals with this disease may often have speech impediments, such as speech delays. Other characteristics of this disease include: epilepsy, congenital and urogenetic defects, microcephaly, corpulence, and psychiatric disorders. From analysis of chromosomal breakpoints, as well as gene sequencing in suggestive cases, Kleefstra and colleagues identified EHMT1 as the causative gene.

This gene is responsible for producing the protein Histone methyltransferase which functions to alter histones. Ultimately, histone methyltransferases are important in deactivating certain genes, needed for proper growth and development. Moreover, a frameshift, missense, or nonsense error in the coding sequence of EHMT1 can result in this condition in an individual.

Jacobsen Syndrome is a rare chromosomal disorder resulting from deletion of genes from chromosome 11 that includes band 11q24.1. It is a congenital disorder. Since the deletion takes place on the q arm of chromosome 11, it is also called 11q terminal deletion disorder. The deletion may range from 5 million to 16 million deleted DNA base pairs. The severity of symptoms depends on the number of deletions. The more deletions there are more severe the symptoms are likely to be. People with Jacobsen syndrome have serious intellectual disabilities, dysmorphic features, delayed development and a variety of physical problems including heart defects. Research shows that almost 88.5% of people with Jacobsen Syndrome have a bleeding disorder called Paris-Trousseau syndrome. [ Jacobsen Syndrome is catastrophic in 1 out of every 5 cases, since children usually die within the first 2 years of life due to heart complications.

Triple-A syndrome or AAA syndrome, also known as achalasia-addisonianism-alacrima syndrome or Allgrove syndrome, is a rare autosomal recessive congenital disorder. In most cases, there is no family history of it. The syndrome was first identified by Jeremy Allgrove and colleagues in 1978. The syndrome involves achalasia, addisonianism (adrenal insufficiency of primary type), and alacrima (insufficiency of tears). Alacrima is usually the earliest manifestation. It is a progressive disorder that can take years to develop the full blown clinical picture.

Recurrent seizures are the most recognizable feature of this syndrome and are most often the first sign of this syndrome. These syndromes are often ongoing and poorly responsive to anti-seizure medications. Most patients develop seizures the first few years of life, but the age of onset ranges from ages 1 to 17. Different types of seizure have been reported in this syndrome. The most common seizure type appears to be brief focal onset epileptic seizures with impairment of consciousness and awareness, known as complex partial seizures. Other features you may see in these complex partial seizures include staring, oral automatisms, unspecified automatic behavior, involuntary motor movements and/or head turning.

Furthermore, many patients have subtle nighttime behavioral changes, such as stretching, rubbing, and turning resembling a nighttime awakening. However, electroencephalography (EEG) studies during these events show abnormal electrical seizure activity, indicating that nocturnal behavioral events are actually subtle nocturnal seizures or non-convulsive status epilepticus. Many of these patients experience their seizures only during sleep. They can have seemingly bizarre features as they originate from the frontal lobe of the brain. Often, individuals with ring chromosome 20 syndrome are initially found to have complex partial seizures of frontal lobe origin, though imaging studies do not show a corresponding structural brain abnormality. In certain patients, these seizures may secondarily generalized.

Individuals from the ages of 0–17 years should be considered for ring 20 chromosome analysis if they have: predominantly complex partial seizures, medically refractory cryptogenic epilepsy, Lennox-Gastaut-like features with no cause identified, frequent subtle nocturnal seizures, an EEG showing prolonged high voltage frontally dominant slowing intermixed with spikes or sharp waves, an EEG showing overlapping features of continuous slow spike and wave discharges in sleep (CSWS) and electrical status epilepticus in sleep (ESES), and/or subsequent cognitive impairment/learning difficulties/mild retardation.These patients will typically have a normal childhood development until onset of epilepsy and lack evidence of dysmorphism or other congenital malformations.

Ring chromosome 20, ring-shaped chromosome 20 or r(20) syndrome is a rare human chromosome abnormality where the two arms of chromosome 20 fuse to form a ring chromosome. The syndrome is associated with epileptic seizures, behaviour disorders and mental retardation.

When not all cells contain a ring chromosome 20, the individual suffers from ring 20 chromosomal mosaicism.Ring Chromosome 20 syndrome is thought to be an underdiagnosed condition. Since chromosomal analysis or karyotype testing is not a routine investigation for patients with epilepsy, the diagnosis of ring chromosome 20 syndrome is typically delayed or unrecognized.

ATR-16 syndrome, also called Alpha-Thalassemia-Intellectual disability syndrome is a rare disease characterized by monosomy on part of chromosome 16.

Miller–Dieker syndrome (abbreviated MDS), Miller–Dieker lissencephaly syndrome (MDLS), and chromosome 17p13.3 deletion syndrome is a micro deletion syndrome characterized by congenital malformations. Congenital malformations are physical defects detectable in an infant at birth which can involve many different parts of the body including the brain, hearts, lungs, liver, bones, or intestinal tract.

MDS is a contiguous gene syndrome - a disorder due to the deletion of multiple gene loci adjacent to one another. The disorder arises from the deletion of part of the small arm of chromosome 17p (which includes both the "LIS1" and "14-3-3 epsilon" genes), leading to partial monosomy. There may be unbalanced translocations (i.e. 17q:17p or 12q:17p), or the presence of a ring chromosome 17.

This syndrome should not be confused with Miller syndrome, an unrelated rare genetic disorder, or Miller Fisher syndrome, a form of Guillain–Barré syndrome.

EEM syndrome (or Ectodermal dysplasia, Ectrodactyly and Macular dystrophy syndrome) is an autosomal recessive congenital malformation disorder affecting tissues associated with the ectoderm (skin, hair, nails, teeth), and also the hands, feet and eyes.

Almost all children with Jacobsen syndrome have Intellectual disabilities, which ranges from mild to moderate depending upon the number of the deletion of genes from the chromosome. Children with intellectual disability take more time than normal to learn new things and acquire new skills. They have problems with assembling new information or adapting to novel situations and associating two events or things together.

Most kids with the syndrome have delayed development including delayed speech, motor disabilities, lack of coordination, which makes even simple activities like sitting, standing and walking difficult for these children. Most kids eventually start speaking but in cases with severe intellectual disability language use is highly restricted.

They have distinctive facial features like:

- Small head (microcephaly)

- Pointed forehead, (trigonocephaly)

- Small ears which are low-set

- Widely-spaced eyes (hypertelorism)

- Droopy eyelids (ptosis)

- Broad nasal bridge

- Abnormally thin upper lips

- Downturned corners of the mouth

- Excess skin covering in the inner corner of eyes (epicanthal folds)

Some children also suffer from behavioural problems like distractibility, hyperactivity, impaired communication and social skills which qualifies them for a diagnosis of ASD and ADHD.

Heart defects are very common in children with Jacobsen Syndrome. 88.5% of people with the disorder have Paris-Trousseau syndrome which is a bleeding disorder and causes a lifelong risk of abnormal bleeding and bruising due to dysfunction in the platelets.

Other symptoms may include eye problems, ear and sinus infections, hearing problems, bone deformities, growth hormone deficiency, gastrointestinal problems, kidney malfunctions etc.