- Microdeletion syndromes
- 1p36 deletion syndrome
- Is there a cure for 1p36 deletion syndrome?
- Does the size of the deletion affect the amount and severity of the symptoms of 1p36 deletion syndrome?
- My son’s deletion size is 2.5 mb. What does this mean?
- My daughter’s geneticist told me her deletion is 1p36.33-1p36.32. What does this mean?
- Will my future children have 1p36 deletion syndrome?
- 1p36 deletion syndrome causes
- 1p36 deletion syndrome inheritance pattern
- 1p36 deletion syndrome symptoms
- 1p36 deletion syndrome diagnosis
- 1p36 deletion syndrome treatment
- 1p36 deletion syndrome prognosis
- 2q37 deletion syndrome
- 3p deletion syndrome
- 15q13.3 microdeletion syndrome
- 16p11.2 deletion syndrome
- 22q11.2 deletion syndrome
- 1p36 deletion syndrome
Microdeletion syndromes are a group of disorders characterized by the deletion of a small chromosomal segment (usually <5 Mb in size) encompassing multiple disease genes, each potentially contributing to the disease phenotype independently 1). The mechanism of disease causation is usually due to haploinsufficiency of certain critical genes of that region. The genetic changes of these microdeletion syndromes are often not detected by the current band resolution using the routine or high resolution karyotyping (2-5 Mb) but require application of molecular cytogenetic techniques like Fluorescence in-situ hybridization (FISH) or the latest array comparative genomic hybridization (CGH) technique.
Fluorescence in-situ hybridization (FISH) is now the standard technique for the diagnosis of common microdeletion syndromes like Prader Willi syndrome, Angelman syndrome, Velocardiofacial (DiGeorge) syndrome, William syndrome etc. It is also possible to diagnose rare syndromes like Wolf Hirschhorn syndrome, Smith Magenis syndrome etc by FISH if the degree of clinical suspicion is high. With the advent of chromosomal microarrays, detection of newer microdeletion syndromes and better characterization of existing syndromes has become possible.
People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.
Resources for locating a genetics professional in your community are available online:
- The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
- The American Board of Genetic Counseling (https://www.abgc.net/about-genetic-counseling/find-a-certified-counselor/) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
- The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
- The American College of Medical Genetics and Genomics (http://www.acmg.net/ACMG/Genetic_Services_Directory_Search.aspx) has a searchable database of medical genetics clinic services in the United States.
1p36 deletion syndrome
1p36 deletion syndrome also known as chromosome 1p36 deletion syndrome, is a disorder that typically causes severe intellectual disability 2). Most affected individuals do not speak, or speak only a few words. They may have temper tantrums, bite themselves, or exhibit other behavior problems. Most have structural abnormalities of the brain, and seizures occur in more than half of individuals with this disorder. Affected individuals usually have weak muscle tone (hypotonia) and swallowing difficulties (dysphagia).
People with 1p36 deletion syndrome have a small head that is also unusually short and wide in proportion to its size (microbrachycephaly). Affected individuals also have distinctive facial features including deep-set eyes with straight eyebrows; a sunken appearance of the middle of the face (midface hypoplasia); a broad, flat nose; a long area between the nose and mouth (philtrum); a pointed chin; and ears that are low-set, rotated backwards, and abnormally shaped.
People with 1p36 deletion syndrome may have vision or hearing problems. Some have abnormalities of the skeleton, heart, gastrointestinal system, kidneys, or genitalia.
1p36 deletion syndrome is believed to affect between 1 in 5,000 and 1 in 10,000 newborns 3). However, this may be an underestimate because some affected individuals are likely never diagnosed.
Is there a cure for 1p36 deletion syndrome?
No, unfortunatley it is not possible to replace missing chromosome pieces. However, treatments are available for many of the problems associated with 1p36 deletion.
The size of the 1p36 deletion, in general, does not predict the severity except for rare cases of very large deletions of 10 million base pairs or more. Most 1p36 deletions are smaller, with the average of about 4 Mb.
My son’s deletion size is 2.5 mb. What does this mean?
A chromosome, and therefore the genes that are on the chromosome, is made of a chemical called deoxyribonucleic acid, or DNA. The DNA is composed of four chemical components called bases. The four bases are adenine, thymine, cytosine, and guanine. These components are symbolized by using one of 4 letters (A, T, C, or G).
DNA is made of two strands, each composed of a long string of the A’s, T’s, C’s, and G’s. The two strands run parallel to one another. In fact, the structure of DNA is often described as a twisted ladder. To create the ladder’s rungs, each of the bases on one strand is paired to a base on the other strand. Chromosome 1 is the largest human chromosome, spanning about 247 million base pairs and representing approximately 8 percent of the total DNA in cells.
So when scientists look at the question above, the 2.5Mb size tells them that the deletion is 2.5 million base pairs. Knowing this information, scientists can examine the genes in the region that are deleted, but this gives them very little information for predicting clinical or medical problems.
My daughter’s geneticist told me her deletion is 1p36.33-1p36.32. What does this mean?
1p36 deletion syndrome is caused by a deletion of genetic material from a specific region in the short (p) arm of chromosome 1. Each chromosome arm is divided into regions, or cytogenetic bands, that can be seen using a microscope with special stains. The cytogenetic bands are labeled p1, p2, p3, etc., counting from the centromere (the middle) out toward the telomeres (the ends). At higher resolutions, sub-bands can be seen within the bands. The sub-bands are also numbered from the centromere out toward the telomere.
Thus, if an individual gets a diagnosis of 1p36.33-1p36.32, it means that there is a deletion within chromosome 1, short (p) arm, in region 3, band 6, and includes sub-bands .33 and .32 of region/band 36. These designations by banded chromosomes are very subjective and arbitrary and do not tell a person how large the deletion is. Microarray CGH is much more precise and tells exactly where, and how large, the deletion is.
Will my future children have 1p36 deletion syndrome?
Most of the time, 1p36 deletion syndrome is not inherited, and is not likely to happen again in the future. Occasionally, a parent may have a chromosome rearrangement that significantly increases the chances of having another child with 1p36 deletion syndrome. All parents of children with 1p36 deletion syndrome should have genetic counseling, and should undergo chromosome analysis and/or FISH testing depending on the size of the deletion. Microarray CGH testing should not be used because it will not pick up “balanced” rearrangements in the parents. The array only tells us if there is a deletion or a duplication.
If you have questions regarding future pregnancies, you should contact a genetics provider. Genetic counselors are health professionals with specialized training and experience in the area of medical genetics and counseling. Clinical geneticists are physicians who diagnose, treat, and counsel patients and families with genetic conditions. Both geneticists and genetic counselors can talk with you about your family history and the implications for future pregnancies. You can locate a genetic counselor through the National Society of Genetic Counselors (https://www.nsgc.org/page/find-a-genetic-counselor). You can also search for a list of genetics clinics in your area through the GeneTetsts Clinic Directory (https://www.ncbi.nlm.nih.gov/gtr/).
1p36 deletion syndrome causes
1p36 deletion syndrome is caused by a deletion of genetic material from a specific region in the short (p) arm of chromosome 1. The signs and symptoms of 1p36 deletion syndrome are probably related to the loss of multiple genes in this region. The size of the deletion varies among affected individuals.
1p36 deletion syndrome inheritance pattern
Most cases of 1p36 deletion syndrome are not inherited. They result from a chromosomal deletion that occurs as a random event during the formation of reproductive cells (eggs or sperm) or in early fetal development. Affected people typically have no history of the disorder in their family.
About 20 percent of people with 1p36 deletion syndrome inherit the chromosome with a deleted segment from an unaffected parent. In these cases, the parent carries a chromosomal rearrangement called a balanced translocation, in which no genetic material is gained or lost. Balanced translocations usually do not cause any health problems; however, they can become unbalanced as they are passed to the next generation. Children who inherit an unbalanced translocation can have a chromosomal rearrangement with extra or missing genetic material. Individuals with 1p36 deletion syndrome who inherit an unbalanced translocation are missing genetic material from the short arm of chromosome 1, which results in birth defects and other health problems characteristic of this disorder.
1p36 deletion syndrome symptoms
All children with 1p36 Deletion Syndrome are unique; however, they can share many of these common characteristics:
- Low muscle tone (congenital hypotonia): Infants with 1p36 Deletion Syndrome often have low muscle tone, which may make it difficult for a newborn to suck and swallow. Hypotonia may also delay sitting, crawling and walking. Muscle tone often improves with age and with physical therapy.
- Seizure disorder: Individuals with 1p36 Deletion Syndrome may have different types of seizures. Most seizure disorders can be controlled with medication.
- Growth/feeding problems: Infants with this condition often have difficulty gaining weight. Some do no gain weight well because they have difficulty sucking and swallowing, while others may not grow well even though they are eating well. Some older children with 1p36 Deletion Syndrome become overweight. Dietary changes, special feeding techniques or other medical interventions may be needed to manage the growth problems associated with this condition.
- Characteristic physical features: Young children with 1p36 Deletion Syndrome tend to look similar. They often have a small head, a large fontanel (soft spot), deep-set eyes, short eye openings, a flat nose with a broad nasal tip, a prominent forehead, low set ears, ear asymmetry, a small mouth and a small pointed chin.
- Developmental delay: Most young children with 1p36 Deletion Syndrome sit up, walk and talk later than usual. Speech is often more delayed than other skills. Many individuals with 1p36 Deletion Syndrome have difficulty talking and may benefit from the use of sign language or assisted communication devices. Early intervention services and intensive speech therapy are recommended to maximize an individual’s abilities.
- Intellectual disability: Older children and adults with 1p36 Deletion Syndrome have some degree of intellectual disability. Some children with 1p36 Deletion Syndrome can talk and assist in their daily care, while others are not verbal and require constant care. Although the degree of intellectual disability may be somewhat dependent on the size of the deletion, there is presently no way to accurately predict what an infant’s IQ will be when they grow up.
- Congenital malformations: Babies with 1p36 Deletion Syndrome may be born with birth defects such as cleft lip, cleft palate, structural heart defects or malformations of the brain. Surgery may help correct some of these problems.
- Cardiomyopathy: Some infants with 1p36 Deletion Syndrome have infantile dilated cardiomyopathy. With cardiomyopathy, the heart is enlarged and doesn’t pump as strongly as it should. When necessary, medication sometimes helps improve cardiac function.
- Hearing loss: Conductive or sensorineural hearing loss occurs quite frequently in children with 1p36 Deletion Syndrome. Treatment for hearing loss is usually the same as it is for children with other causes of hearing loss.
- Vision or eye problems: A number of different types of vision and eye problems have been reported in children with 1p36 Deletion Syndrome. Vision problems can usually be improved with glasses or other interventions.
- Thyroid problems: Children with 1p36 Deletion Syndrome seem to be at an increased risk of developing thyroid problems, the most common being hypothyroidism. Hypothyroidism occurs when the thyroid gland does not make enough of a hormone that is necessary for growth and development. When diagnosed, hypothyroidism can be treated successfully with medication.
- Behavior problems: A number of behavior problems have been reported in children with 1p36 Deletion Syndrome. These include self-injuring behavior, banging or throwing objects, hitting people and screaming episodes. Child psychiatrists or psychologists can recommend strategies and medications that may help with behavior problems if they arise.
- Rare complications: Additional, less common findings reported in children with 1p36 Deletion Syndrome include early onset of puberty (precocious puberty), abnormal curvature of the spine (scoliosis), minor vertebral abnormalities, and testes that have not descended into the scrotum at birth (cryptochirdism). Other uncommon medical complications may include neuroblastoma (a type of abdominal tumor that occurs almost exclusively in early childhood). Neuroblastoma is rare and has only been reported in a few children with 1p36 Deletion Syndrome or a chromosome rearrangement involving 1p36.
Bedell et al. 4) cited reports of 11 children who have been described with 2 or more syndromes with overlapping phenotypes and variations of the following features: short stature (9 of 10), prominent forehead (9 of 9), brachycephaly (7 of 7), microcephaly (10 of 11), midface hypoplasia (10 of 10), prominent jaw/chin (11 of 11), dysplastic pinna (6 of 7), hearing loss (3 of 11), congenital heart disease (7 of 11), hypotonia (11 of 11), DD/MR (11 of 11), facial clefting (4 of 11), and early demise (3 of 11). All patients were associated with a deletion of the terminal short arm of chromosome 1.
Based on the 13 subjects described by Shapira et al. 5), facial characteristics of the syndrome include deep-set eyes, flat nasal bridge, asymmetric ears, and pointed chin. Additional clinical characteristics include seizures, cardiomyopathy, developmental delay, and hearing impairment 6).
Heilstedt et al. 7) reported 62 patients with monosomy 1p36. Thirty were systematically examined through a specific protocol including hearing evaluations, palatal and ophthalmologic examinations, echocardiograms, neurologic assessments, and thyroid function tests. Orofacial clefting anomalies were present in 5 of 30 (17%); hypermetropia was present in 20 of 30 (67%). Six of 30 (20%) had hypothyroidism. All 30 had developmental delay and mental retardation. Twenty-six of 30 (87%) had hypotonia. Oropharyngeal dysphasia was present in 21 of 29 (72%). A history of dilated cardiomyopathy in infancy was present in 7 subjects (23%). In none did the condition worsen over time. Thirteen subjects (43%) had a structural heart defect, most frequently patent ductus arteriosus. Some hearing impairment was present in 82% of the subjects, being sensorineural type in almost all.
Tan et al. 8) reported a 16-year-old boy with features of Cantu syndrome who was found to have a distal 1p36 deletion. The boy also had features not previously described in either syndrome, including hypercholesterolemia, type II diabetes, recurrent bony fractures, and nonalcoholic steatohepatitis.
Neal et al. 9) reported a 3-year-old girl who had developmental delay, Duane syndrome anomaly, hearing loss, mild dysmorphic facial features including posteriorly rotated and slightly low-set ears and a broad nasal bridge, and scoliosis. MRI brain imaging revealed left periventricular nodular heterotopia, truncation of the rostrum of the corpus callosum, slight ventricular enlargement, and patchy areas of hyperintensity consistent with delayed myelination. FISH analysis detected a deletion of 1p36 with loss of heterozygosity between D1S468 and D1S450, indicating at most a 9.6-Mb deletion region on 1pter-p36.22. Sequencing of the FLNA gene, which has been shown to cause PVNH1, revealed no alterations in the coding region in this patient.
Battaglia et al. 10) evaluated 60 patients with the 1p36 deletion syndrome (41 females and 19 males). Microcephaly was reported in 95% of patients, and all patients had straight eyebrows, deep-set eyes, midface hypoplasia, broad nasal root/bridge, long philtrum, and pointed chin. Other dysmorphic features included microbrachycephaly (65%), epicanthus (50%), large late-closing anterior fontanel (77%), and posteriorly rotated low-set abnormal ears (40%). Brachy/camptodactyly and short feet were prominent. Heart defects were present in 71%, including 23% with noncompaction cardiomyopathy. Other findings included visual inattentiveness (64%), visual abnormalities (52%), sensorineural deafness (28%), skeletal abnormalities (41%), abnormal genitalia (25%), and renal abnormalities (22%). Eighty-eight percent had central nervous system anomalies: 44% had seizures and 95% had hypotonia. All patients had developmental delay with poor or absent speech, and 47% had a behavior disorder. Gradual developmental progress was observed in all patients over time.
Rudnik-Schoneborn et al.11) reported an 8-month-old girl with microcephaly and a midline brain malformation who had an interstitial deletion of 1p36 on conventional chromosome analysis; FISH and array CGH analysis documented an 8.7-Mb deletion encompassing 1p36.23-p36.13. Brain MRI at age 5 months revealed agenesis of the anterior commissure and rostral corpus callosum and partial agenesis of the septum pellucidum. The authors stated that this structural brain defect had not previously been described in proximal 1p36 deletion.
Bursztejn et al. 12) reported an 8-year-old girl with an initial clinical diagnosis of Aicardi syndrome who was subsequently found to carry a de novo 11.73-Mb terminal deletion of chromosome 1p36, thus revising the diagnosis. She had onset of infantile spasms at age 3 months, bilateral pupillary coloboma, agenesis of the corpus callosum, and delayed psychomotor development. Other features included deep-set eyes, low-set and posteriorly rotated ears, brachydactyly, and hypertrichosis. She also had interatrial and trabeculated interventricular communications. The deletion was found to occur on the maternal chromosome during oogenesis. The report emphasized the phenotypic overlap between the 2 disorders.
D’Angelo et al. 13) described 9 unrelated patients with de novo deletions of distal 1p36 ranging in size from 2.2 to 10.2 Mb. Four deletions that could be studied occurred on the maternal allele. Four of the patients were ascertained from a larger group of 154 patients with psychomotor delay associated with hyperphagia and obesity, suggesting that this is an additional variable feature of monosomy 1p36. Five of the patients were ascertained from a larger group of 83 patients suspected to have monosomy 1p36 due to mental retardation. Three of the patients with obesity did not have the typical facial features of monosomy 1p36 and had slightly milder cognitive impairment. D’Angelo et al. 14) suggested involvement of the PRKCZ gene, which was deleted in all patients, but also noted the possibility of a position effect.
Dod et al. 15) reported a 25-year-old man with monosomy 1p36 who developed symptoms of left ventricular noncompaction as an adult. In infancy and childhood, he had severe developmental delay, facial dysmorphism, seizures, and a cardiomyopathy with a low ejection fraction (15 to 20%). He also had scoliosis and spastic quadriparesis.
1p36 deletion syndrome diagnosis
1p36 deletion syndrome is diagnosed by special laboratory testing. The deletion may be identified in the laboratory with high-resolution chromosome analysis or a test called FISH (fluorescent in-situ hybridization). FISH is used to detect missing pieces of chromosome material that are too small to be seen with a microscope during routine chromosome analysis. Recently, a new technology, called microarray CGH (Comparative Genomic Hybridization) has been developed. A microarray analysis compares a person’s DNA to “control DNA”. The control DNA comes from a person that doesn’t have a chromosome abnormality. A chromosome change is identified when there are differences between a person’s DNA and the control DNA. A microarray is currently the best and most accurate test to diagnose 1p36 deletion syndrome.
1p36 deletion syndrome treatment
There is no cure for 1p36 deletion syndrome. Treatment depends on the symptoms, and may include rehabilitation/educational programs, antiepileptic medication, and standard treatment for heart, kidney, eye, hearing or bone problems.
1p36 deletion syndrome is a recently recognized condition, there are no standardized health care guidelines available. Recommendations, however, often include the following:
- An echocardiogram (ultrasound) of the heart to determine if there is a heart defect or cardiomyopathy
- An eye exam to determine if there are any vision or eye problems
- A complete hearing test (including high frequencies) to detect hearing problems, many times for young children this is in the form of an ABR (Auditory Brainstem Response) test
- A CT scan or MRI of the brain to rule our brain malformations
- Evaluation of feeding and growth as a newborn, and at regular intervals during childhood
- Developmental assessments with speech, physical and occupational therapists
- Blood tests for thyroid dysfunction at birth and six months of age, and then annually
1p36 deletion syndrome prognosis
The severity and nature of signs and symptoms of chromosome 1p36 deletion syndrome varies between affected individuals, so it is difficult to predict the long-term outlook for an individual child 16). Generally, affected individuals do survive well into adult life 17). There is only one study 18) to date in which the natural history of 1p36 deletion syndrome has been investigated with a follow-up spanning 18 years. Although this study does not specifically address life expectancy, it does contain substantial information regarding the natural history of the condition. This study reported a gradual acquisition of adaptive behaviors (where inappropriate or unconstructive behavior is replaced by more constructive behavior), improved social interaction and attainment of gross motor and fine motor skills. An improvement in communication skills and verbal comprehension was also seen, however, children will normally need lifelong care and medical support and will at best achieve only limited independence. Parental experience suggests that a small minority of children achieve toilet timing or toilet training. Many can help get themselves dressed by pushing their arms through sleeves and a few learn to undress but almost all need a carer for dressing. Some children are able to brush their teeth and wash their hands and faces, although the majority need help with these tasks.
2q37 deletion syndrome
2q37 deletion syndrome also called Albright hereditary osteodystrophy-like syndrome or brachydactyly-mental retardation syndrome, is a condition that can affect many parts of the body. Most babies with 2q37 deletion syndrome are born with weak muscle tone (hypotonia), which usually improves with age 19). Other neurological abnormalities that are common in affected individuals include mild to severe intellectual disability; delayed development of motor skills, such as sitting and walking; and behavioral problems. About 25 percent of people with this condition have autism spectrum disorder, a developmental condition that affects communication and social interaction.
Unusual physical features are also common in people with 2q37 deletion syndrome. About half of affected individuals have unusually short fingers and toes (brachydactyly), often with abnormally short fourth toes that may overlap the other toes. Additional features of this condition may include short stature, obesity, or sparse hair. Many people with 2q37 deletion syndrome have characteristic facial features that can include a prominent forehead, a low frontal hairline, thin eyelids, skin folds covering the inner corner of the eyes (epicanthal folds), outside corners of the eyes that point upward (upslanting palpebral fissures), a small nose, a small mouth with thin lips, a smooth space between the upper lip and nose (smooth philtrum), prominent cheekbones, a large chin, and minor ear abnormalities.
Other features of 2q37 deletion syndrome can include seizures and an inflammatory skin disorder called eczema. Some affected individuals have malformations of the brain, heart, gastrointestinal system, kidneys, or genitalia. A few people with 2q37 deletion syndrome develop a rare form of kidney cancer called Wilms tumor.
2q37 deletion syndrome appears to be a rare condition, although its exact prevalence is unknown 20). At least 115 cases have been reported worldwide.
2q37 deletion syndrome causes
2q37 deletion syndrome is caused by deletions of genetic material from a specific region in the long (q) arm of chromosome 2. The deletions occur near the end of the chromosome at a location designated 2q37. The size of the deletion varies among affected individuals, with most affected people missing 2 million to 9 million DNA building blocks (also written as 2 Mb to 9 Mb).
Researchers are working to identify all of the genes whose loss contributes to the features of 2q37 deletion syndrome. Many of these genes have not been well characterized. However, genes in this region appear to be critical for the normal development of many parts of the body.
Researchers have determined that loss of a particular gene on chromosome 2, called HDAC4, is likely to account for many of the syndrome’s characteristic signs (such as intellectual disability and skeletal abnormalities). While the deleted segment in 2q37 deletion syndrome varies in size, it always contains the HDAC4 gene. Additionally, a few people with mutations in only the HDAC4 gene have many of the features of 2q37 deletion syndrome. It is unclear what role the other genes on 2q37 play in this disorder.
2q37 deletion syndrome inheritance pattern
Most cases of 2q37 deletion syndrome are not inherited. They result from a chromosomal deletion that occurs as a random event during the formation of reproductive cells (eggs or sperm) or in early fetal development. Affected people typically have no history of the disorder in their family.
Rarely, an affected individual inherits a copy of chromosome 2 with a deleted segment from an affected parent. In these cases, the parent is usually less severely affected than the child, for reasons that are unknown. When an affected child inherits a chromosomal deletion from a parent, it is inherited in an autosomal dominant pattern, which means one copy of the altered chromosome in each cell is sufficient to cause the disorder.
2q37 deletion syndrome symptoms
Most babies with 2q37 deletion syndrome are born with low muscle tone (hypotonia), which usually improves with age. About 25% of those with this syndrome have autism, a developmental condition that affects communication and social interaction. The characteristic facial features include a prominent forehead, highly arched eyebrows, deep-set eyes, a flat nasal bridge, a thin upper lip, and minor ear abnormalities 21).
Other features can include 22):
- Short stature
- Unusually short fingers and toes (brachymetaphalangy), especially of the fingers 3-5
- Sparse hair
- Heart defects
- A skin disorder called eczema
A few people with 2q37 deletion syndrome have a rare form of kidney cancer called Wilms tumor. Some individuals with 2q37 deletion syndrome can also have malformations of the brain, gastrointestinal system, kidneys, and/or genitalia 23).
Wilson et al. 24) reported 5 unrelated patients with a phenotype resembling the physical anomalies found in Albright hereditary osteodystrophy. Variable features included short stature, stocky build, mental retardation, brachymetaphalangia, and eczema. Soft tissue ossification was absent, and there were no abnormalities in parathyroid hormone or calcium metabolism. These patients, unlike some patients with Albright hereditary osteodystrophy features, had normal levels of Gs-alpha.
Williams et al. 25) reported 6 unrelated patients with brachydactyly-mental retardation syndrome, including 4 with deletions of chromosome 2q37 that involved the HDAC4 gene and 2 with point mutations in the HDAC4 gene. Several of the cases had been referred on suspicion of having the Smith-Magenis syndrome and 4 patients had previously been reported by Wilson et al. 26), Aldred et al. 27), and Williams et al. 28). The 2 patients with HDAC4 point mutations were described in detail. The first patient was a French Canadian woman, born of nonconsanguineous parents, who showed feeding difficulties in infancy and progressively delayed psychomotor development. Subvalvular aortic stenosis was identified at 4 months, and she received a mitral valve replacement and permanent pacemaker at age 5 years. Physical examination at age 13.5 years showed dysmorphic features, including midface hypoplasia, broad face and nose, brachycephaly, frontal bossing, downturned lower lip, and upslanted eyes. She also had hyporeflexia, a wide-based gait, and sensorineural hearing loss. Behavioral features included decreased sensitivity to pain, onychotillomania, hyperactivity, a decreased attention span, and sleep abnormalities. At age 25, she was obese. She had with bilateral proximal placement of the third, fourth, and fifth fingers, bilateral proximally placed fourth toes, and bilateral widely spaced first, second, and third toes. Radiographs confirmed brachydactyly type E (BDE), with shortened metacarpals and metatarsals. Family history was unremarkable. The second patient was a 16-year-old Caucasian female with obesity and intellectual disability. She had poor feeding in infancy and delayed psychomotor development. Dysmorphic features included a small chin, large asymmetrically placed ears, bitemporal narrowing, and narrow palpebral fissures. Neurologic and behavioral abnormalities included aggressive tantrum-like behavior, decreased sensitivity to pain, head banging, self-biting, skin picking resulting in scarring, stereotypies, food-seeking behaviors, and sleep disturbances. Musculoskeletal features include hypotonia, hypermobility, pes planus, and type E brachydactyly with mild shortening of metacarpals and metatarsals three through five. The 4 other patients with chromosome 2q37 deletions had similar features and the absence of hearing loss and congenital heart malformation. Variable features included short stature in 2, seizures in 1, and obesity/overweight in 2.
Villavicencio-Lorini et al. 29) reported a 3-generation family in which the proband, her mother, and her maternal grandmother had very mild developmental delay and dysmorphic facial features associated with an inherited heterozygous interstitial deletion of chromosome 2q37.3. None of the individuals had brachydactyly. Dysmorphic features included coarse facies with high-arched eyebrows, deep-set eyes, narrow palpebral fissures, broad, depressed nasal bridge, and everted full lips. The proband had sleeping difficulties and aggressive behavior. The deletion was about 800 kb and included the HDAC4, FLJ43879, and TWIST2 genes. Villavicencio-Lorini et al. 30) concluded that the absence of brachydactyly type E in this family was consistent with previous observations that brachydactyly type E is a variable clinical feature associated with 2q37 deletions, and that HDAC4 haploinsufficiency is not fully penetrant for brachydactyly type E (BDE).
Ogura et al. 31) reported 2 unrelated male patients with different interstitial deletions of 2q37.3 involving multiple genes. One patient (patient 1) was a 16-year-old Japanese boy with BDE, dysmorphic facial features, delayed psychomotor development, and moderate intellectual disability. He had a heterozygous 3.2-Mb deletion that included the HDAC4 gene. The other patient (patient 2) was a 5-year-old Japanese boy with mildly delayed language and mild behavioral issues, including obsessive tendencies and mild attention impairment, as well as poor fine motor skills; he did not have brachydactyly type E (BDE). He had a 2.3-Mb deletion that did not include the HDAC4 gene. Both patients also had disabilities in visuospatial perception. All 4 parents declined genetic analysis.
Jean-Marcais et al. 32) reported a father and his 3 children who had brachydactyly type E, short stature, and normal cognitive development associated with an inherited heterozygous interstitial deletion of 2q37.3. The proband, who was one of the children, had bilateral shortening of metacarpals IV and V, bilateral shortening of metatarsals III, IV, and V, and mild short stature. Her brother had brachymetatarsy without brachymetacarpy, and her 3-year-old sister had short stature without visible brachymetacarpy or brachymetatarsy. The father had shortening of metacarpals and metatarsals IV and V, and mild short stature. The father and proband had similar dysmorphic features, including depressed nasal bridge, hypoplastic nasal alae, sparse arched eyebrows, and prominent columella. Several family members on the father’s side reportedly had short stature and brachymetarcarpy/brachymetatarsy. None of the individuals had intellectual disability or behavioral abnormalities. The deletion was between 491 and 813 kb and included the HDAC4 and TWIST2 genes, as well as 2 noncoding RNAs (MGC16025 and FLJ43879) and 3 microRNAs (MIR4269, MIR4441, and MIR4440). DNA from additional possibly affected family members on the paternal side was not available. The report indicated that haploinsufficiency of HDAC4 and the surrounding critical region is not always associated with cognitive defects.
2q37 deletion syndrome diagnosis
To establish the extent of disease in an individual diagnosed with the 2q37 microdeletion syndrome, the following evaluations are recommended:
- Complete medical history to include evidence of any congenital malformations, seizure disorder, or behavioral problems
- Complete physical and dysmorphology examination
- Determination of head circumference, height, weight, and other anthropometric measurements
- Specialty evaluation of obesity or failure to thrive
- Multidisciplinary developmental and neurologic evaluation to assess motor and cognitive skills as well as autism, autism spectrum behaviors, and other behavioral issues
- Echocardiogram to evaluate for congenital cardiac anomaly
- Renal ultrasound examination to evaluate for possible Wilms tumor, renal malformation, or other renal problems
- Ophthalmology evaluation for strabismus and/or refractive errors
- Audiologic assessment for possible hearing loss
- Brain imaging studies (MRI, CT scan) in individuals with abnormal neurologic findings
- EEG for evaluation of seizures and treatment monitoring
- X-ray to evaluate for the presence of scoliosis and skeletal anomalies examination. While the clinical implications of osteopenia have not been studied in the 2q37 microdeletion syndrome, clinicians should be aware that this is a common finding. X-rays should be performed at diagnosis and should be repeated as warranted by clinical examination. The youngest individual with osteopenia in the authors’ series is age three years.
- Consultation with a clinical geneticist and/or genetic counselor
Chromosome analysis confirms the diagnosis of 2q37 deletion syndrome in 80%-85% of affected individuals. In about 15%-20% of cases the small size of the deleted region can only be detected using deletion analysis (which relies on a variety of methods). In some individuals, 2q37 microdeletion syndrome results from chromosome rearrangements involving 2q37 (e.g., chromosome 2 inversion, ring chromosome 2, or translocation between chromosome 2 and another chromosome). Mutation of HDAC4 has been proposed as causative for most of the features of the 2q37 microdeletion syndrome. Several affected individuals without microdeletions had inactivating mutation of HDAC4, a gene in the 2q37 deleted region, leading to the proposal that mutation of this gene may be causative for most of the features of the 2q37 microdeletion syndrome.
2q37 deletion syndrome treatment
Multidisciplinary care by specialists in the following fields is often required: clinical genetics, speech pathology, occupational and physical therapy, child development, neurology, cardiology, gastroenterology, nutrition/feeding, ophthalmology, and audiology.
Medical care may be coordinated by a clinical geneticist or other health care professional skilled at managing patients with complex needs.
Infants benefit from enrollment in an early-intervention program. Most school-age children benefit from an individualized educational program (IEP) with input from a multispecialty group of physical, occupational, and speech therapists with pediatric assessment.
Ongoing routine primary care; periodic reevaluation by a clinical geneticist to provide new recommendations and information about the syndrome; periodic neurodevelopmental and/or developmental/behavioral pediatric evaluation to assist in the management of cognitive and behavioral problems. Screening for renal cysts at age four years and again at puberty is suggested. For young children with a deletion that includes 2q37.1, screening for Wilms tumor can be considered.
3p deletion syndrome
3p deletion syndrome also called 3p partial monosomy syndrome, is a condition that results from a chromosomal change in which a small piece of chromosome 3 is deleted in each cell. The deletion occurs at the end of the short (p) arm of the chromosome. This chromosomal change often leads to intellectual disability, developmental delay, and abnormal physical features 33).
Individuals with 3p deletion syndrome typically have severe to profound intellectual disability. Most have delayed development of language skills as well as motor skills such as crawling and walking. While affected individuals learn to walk in childhood, their language ability usually remains limited. Some individuals with 3p deletion syndrome have obsessive-compulsive disorder (OCD) or features of autism spectrum disorders, which are conditions characterized by impaired communication and social interaction.
The physical signs and symptoms of 3p deletion syndrome vary greatly. Many affected individuals have slow growth, an abnormally small head (microcephaly), a small jaw (micrognathia), droopy eyelids (ptosis), malformed ears or nose, and widely spaced eyes (hypertelorism). Other frequent features include skin folds covering the inner corner of the eyes (epicanthal folds), extra fingers or toes (polydactyly), and an opening in the roof of the mouth (cleft palate). Additionally, individuals with 3p deletion syndrome may have seizures, weak muscle tone (hypotonia), intestinal abnormalities, or congenital heart defects.
3p deletion syndrome is likely a rare disorder; at least 30 cases have been described in the scientific literature 34).
3p deletion syndrome causes
3p deletion syndrome is caused by deletion of the end of the small (p) arm of chromosome 3. The size of the deletion varies among affected individuals, ranging from approximately 150,000 DNA building blocks (150 kilobases or 150 kb) to 11 million DNA building blocks (11 megabases or 11 Mb). The deletion can include between 4 and 71 known genes. In some individuals, the deletion involves material near the end of the chromosome but does not include the tip (the telomere).
In most people with chromosome 3p- syndrome, the deletion occurs as a new mutation (called a de novo mutation) and is not inherited from a parent. De novo mutations are due to a random error that occurs during the formation of egg or sperm cells, or shortly after conception. In a few cases, the deletion is inherited from a parent.
The signs and symptoms related to 3p deletion syndrome result from the loss of genes in the 3p region. It is difficult to determine which genes may be responsible for which specific features of 3p deletion syndrome because of the variability in both the size of the deletion and in the signs and symptoms of the condition among affected individuals. Multiple genes at the end of chromosome 3 appear to play a role in neurological development, but because not all people with 3p deletion syndrome are missing the same genes, it is difficult to pinpoint which ones influence the cognitive symptoms. It is likely that the loss of multiple genes contribute to the different physical abnormalities.
3p deletion syndrome inheritance pattern
Most cases of 3p deletion syndrome are not inherited. The deletion occurs in one chromosome, most often as a random event during the formation of reproductive cells (eggs or sperm) or in early fetal development. In these cases, affected people have no history of the disorder in their family.
In rare cases, 3p deletion syndrome is inherited, usually from a mildly affected parent. The deletion can also be inherited from an unaffected parent who carries a chromosomal rearrangement between chromosome 3 and another chromosome. This rearrangement is called a balanced translocation. No genetic material is gained or lost in a balanced translocation, so these chromosomal changes usually do not cause any health problems. However, translocations can become unbalanced as they are passed to the next generation. Children who inherit an unbalanced translocation have a chromosomal rearrangement with extra or missing genetic material. Individuals with 3p deletion syndrome associated with an unbalanced translocation are missing genetic material from the short arm of chromosome 3, which results in the signs and symptoms of this disorder.
3p deletion syndrome symptoms
The signs and symptoms of chromosome 3p deletion syndrome and the severity of the condition depend on the exact size and location of the deletion and which genes are involved. Some affected people appear to have no features or mild features, while others are more severely affected.
Common symptoms shared by many people with 3p deletion syndrome include 35):
- Growth problems both before and after birth
- Feeding difficulties
- Developmental delay
- Poor muscle tone (hypotonia)
- Intellectual disability
- Distinctive facial features
- Microcephaly and/or unusual head shape
- Autism spectrum disorder
Other features that may be seen include cleft palate; extra fingers and/or toes; gastrointestinal abnormalities; seizures; hearing impairment; kidney problems; and/or congenital heart defects 36).
3p deletion syndrome diagnosis
There are several different specialized tests that can be used to diagnose a chromosome 3p- syndrome. These include:
- Karyotype – a karyotype is a laboratory test that produces an image of a person’s chromosomes. This test can be used to diagnose large deletions.
- FISH – a laboratory technique that is used to detect and locate a specific DNA sequence on a chromosome. During FISH, a chromosome is exposed to a small DNA sequence called a probe that has a fluorescent molecule attached to it. The probe sequence binds to its corresponding sequence on the chromosome. This test can be used in combination with karyotyping for deletions that are too small to be seen on karyotype, alone. However, FISH is only useful if the person ordering the test suspects there is a duplication of a specific region of 3p.
- Array CGH – a technology that detects deletions that are too small to be seen on karyotype.
3p deletion syndrome treatment
Treatment is based on the signs and symptoms present in each person. Because chromosome 3p- syndrome affects many different systems of the body, medical management is often provided by a team of doctors and other healthcare professionals. Treatment for this deletion varies based on the signs and symptoms present in each person. For example, children with delayed motor milestones (i.e. walking) and/or muscle problems may be referred for physical or occupational therapy. Severe feeding difficulties may be treated temporarily with a nasogastric tube or a gastrostomy tube to ensure that a baby or child gets enough nutrients. Certain medications may be prescribed to treat seizures. Special education services are often necessary for children with intellectual disability. Surgery may be required to treat certain physical abnormalities such as cleft palate or congenital heart defects, if present 37).
Please speak to your healthcare provider if you have any questions about your personal medical management plan.
3p deletion syndrome prognosis
The long-term outlook (prognosis) for people with chromosome 3p deletion syndrome varies from person to person. The severity of the condition and the associated signs and symptoms largely depend on the size and location of the deletion and the genes involved.
15q13.3 microdeletion syndrome
15q13.3 microdeletion also known as 15q13.3 microdeletion syndrome is a chromosomal change in which a small piece of chromosome 15 is deleted in each cell 38). The deletion occurs on the long (q) arm of the chromosome at a position designated q13.3. This chromosomal change increases the risk of intellectual disability, seizures, behavioral problems, autism spectrum disorders, and schizophrenia 39). Behavioral problems are common and mainly comprise poor attention span, hyperactivity, mood disorder, and aggressive and/or impulsive behavior. Intellectual disability, observed in about half of the individuals with this recurrent deletion, is usually mild but can be moderate to severe. However, some people with a 15q13.3 microdeletion do not appear to have any associated features 40).
About half of all people with a 15q13.3 microdeletion have learning difficulties or intellectual disability, which is usually mild or moderate. Many of these individuals have delayed speech and language skills. 15q13.3 microdeletion also appears to be a major risk factor for recurrent seizures (epilepsy); about one-third of people with this chromosomal change have epilepsy.
15q13.3 microdeletion has also been associated with behavioral problems, including a short attention span, aggression, impulsive behavior, and hyperactivity. Some people with a 15q13.3 microdeletion have been diagnosed with developmental disorders that affect communication and social interaction (autism spectrum disorders). This chromosomal change may also be associated with an increased risk of psychiatric disorders, particularly schizophrenia. Other signs and symptoms of 15q13.3 microdeletion can include heart defects, minor abnormalities involving the hands and arms, and subtle differences in facial features.
Some people with a 15q13.3 microdeletion do not have any of the intellectual, behavioral, or physical features described above. In these individuals, the microdeletion is often detected when they undergo genetic testing because they have an affected relative. It is unknown why a 15q13.3 microdeletion causes cognitive and behavioral problems in some individuals but few or no health problems in others.
15q13.3 microdeletion likely occurs in about 1 in 40,000 people in the general population. It appears to be more common in people with intellectual disability, epilepsy, schizophrenia, or autism spectrum disorders.
The clinical picture should guide treatment. Early educational interventions are recommended in patients with cognitive impairment and autism. Epilepsy, autism and/or schizophrenia should be treated according to standard guidelines. Cardiac ultrasound should be performed in all carriers to exclude a congenital heart defect. Management in healthy carriers is not necessary, although medical awareness of signs that may become apparent later in life, e.g. schizophrenia, is recommended.
15q13.3 microdeletion syndrome causes
Most people with a 15q13.3 microdeletion syndrome are missing a sequence of about 2 million DNA building blocks (base pairs), also written as 2 megabases (Mb), at position q13.3 on chromosome 15. The exact size of the deleted region varies, but it typically contains at least six genes. This deletion usually affects one of the two copies of chromosome 15 in each cell.
The signs and symptoms that can result from a 15q13.3 microdeletion are probably related to the loss of one or more genes in this region. However, it is unclear which missing genes contribute to the specific features of the disorder. Because some people with a 15q13.3 microdeletion have no obvious signs or symptoms, researchers believe that other genetic or environmental factors may also be involved.
15q13.3 microdeletion syndrome inheritance pattern
15q13.3 microdeletion syndrome is inherited in an autosomal dominant pattern, which means one copy of the deleted region on chromosome 15 in each cell is sufficient to increase the risk of intellectual disability and other characteristic features.
In about 75 percent of cases, individuals with 15q13.3 microdeletion inherit the chromosomal change from a parent. In the remaining cases, 15q13.3 microdeletion occurs in people whose parents do not carry the chromosomal change. In these individuals, the deletion occurs most often as a random event during the formation of reproductive cells (eggs and sperm) or in early fetal development.
15q13.3 microdeletion syndrome signs and symptoms
Sharp et al. 41) reported a recurrent microdeletion syndrome characterized by mental retardation, epilepsy, and variable dysmorphism of the face and digits. They described 9 affected individuals, including 6 probands: 2 with de novo deletions, 2 who inherited the deletion from an affected parent, and 2 with unknown inheritance. Features shared among 3 or more individuals included hypertelorism, upslanting palpebral fissures, prominent philtrum with full everted lips, short and/or curved fifth finger, and short fourth metacarpals. Skeletal and/or joint defects of the hand were observed in 7 of the 9 individuals. Seizures or abnormal electroencephalograms were reported in 7 of the 9 individuals. Sharp et al. 42) recommended that testing for the 15q13.3 deletion syndrome should be considered in individuals with unexplained mental retardation, seizures, and mild dysmorphic features.
Ben-Shachar et al. 43) identified 20 individuals, including 14 children and 6 parents from 12 families, with microdeletions of chromosome 15q13.3. Clinical features were variable, but 12 of 14 children had developmental delay, mental retardation, or borderline IQ. At least 6 children had symptoms within the range of autism spectrum disorder. Nine children demonstrated abnormal behavior, including aggressiveness, repeated head banging, and/or attention deficit hyperactivity disorder. Only 1 child had seizures. The facial appearance was variable and ranged from near normal to moderately dysmorphic. Common facial features included hypertelorism, short philtrum, and everted and thick upper lip. Mild digital aberrations, including brachydactyly and clinodactyly, were observed in 5 patients. Family studies showed that the deletion was inherited in 7 of 8 families where determinable. Two fathers with the deletion had learning disability and bipolar disorder, whereas the 4 other parents with the deletion had no neurologic or psychiatric abnormalities, indicating incomplete penetrance. The last family had no parental samples available, but affected sibs suggested familial inheritance. Of note, 6 of the 14 children had been adopted, suggesting that adoption may have been related to cognitive, psychiatric, or social difficulties in their biologic parents who may have carried the deletion. Ben-Shachar et al. 44) noted the wide range and heterogeneity of phenotypic expression reported for this deletion.
Miller et al. 45) identified 5 unrelated patients with chromosome 15q13.2-q13.3 deletion involving breakpoints 4 and 5 (BP4-BP5) identified by array comparative genomic hybridization (CGH). All had subtle dysmorphic features, impaired language skills, and developmental delay. One patient had mental retardation, and 4 had below average to average intelligence, including 2 with significant learning disability. The patients often had oromotor dyspraxia with disarticulation. Some had mild motor delay. Most had a diagnosis of an autism spectrum disorder or autistic features, as well as difficulties with attention, hyperactivity, mood regulation, and impulsive behaviors. Two patients inherited the microdeletion from a mother with learning difficulties. The deletion sizes ranged from 1.50 to 1.93 Mb.
Shinawi et al. 46) identified the same 680-kb deletion of chromosome 15q13.3 in 10 individuals from 4 families. One family of European ancestry contained 6 affected individuals. The proband was an 8-year-old boy with obesity, severe mental retardation, and mild facial dysmorphism, including epicanthal folds, anteverted nares, and a thin upper lip. Although he did not have seizures, EEG was abnormal. The deletion was present in his mother, 2 sibs, maternal aunt, and maternal grandmother. The mother and her sister had a history of mental retardation and epilepsy, and his sibs had global developmental delay. In a second family, the proband was a 21-month-old girl with impaired growth and severe global developmental delay. Her mother, who also carried the deletion, was reported to have normal intelligence, but had a history of epilepsy since age 5. Another unrelated patient with the deletion had mild mental retardation, attention deficit hyperactivity disorder, and aggressive behavior without seizures, and yet another had global developmental delay, hypotonia, and failure to thrive. In all, 4 of 10 individuals with the 680-kb deletion had seizures or EEG abnormalities, and 9 of 10 showed developmental delay and/or mental retardation.
Van Bon et al. 47) reported 18 probands with heterozygous deletion of chromosome 15q13.1-q13.3. Sixteen of the patients who had a BP4-BP5 deletion were detected among a larger cohort of 6,624 persons referred for mental retardation and/or congenital defects, yielding a rate of 0.24%. One of the most severely affected individuals was a girl who had onset of seizures at age 1 month, showed delayed psychomotor development, and was severely mentally retarded with poor speech, apathetic behavior, and sleeping problems. She also had short stature and microcephaly. Dysmorphic features included asymmetric skull with bitemporal narrowing, bristly hair, synophrys, blepharophimosis, squint, bulbous nasal tip, and folded helices. Other features included tapering fingers, deep palmar creases, hypoplastic fourth and fifth toes, an external rotation of the feet, and multiple pigmented nevi. Brain MRI showed showed several abnormalities, such as an arachnoidal cyst, parenchymal hypoplasia, dislocation of cerebellar structures, and mild hypogenesis of the corpus callosum. Microarray analysis showed a deletion between BP4 and BP5, which was also present in the normal mother. At the other end of the phenotypic spectrum was a 9-year-old girl with normal cognitive development who presented at birth with tetralogy of Fallot and triphalangeal thumb. She had mild hypertelorism. Microarray analysis showed a BP4-BP5 deletion with uncertain inheritance. Overall, 16 of 18 probands had some degree of cognitive impairment varying from mild learning problems to all levels of mental retardation. Behavioral problems were frequent (59%), and comprised poor attention span, hyperactivity, and aggressive/impulsive behavior. Less common features were hypotonia (47%), prominent nasal tip (35%), short stature (24%), strabismus (18%), large ears (24%), cardiac defects (17%), fifth finger clinodactyly (24%), and pigmented nevi (18%). However, there were a total of 13 relatives who carried the same deletion as the proband, and all of these frequencies would be significantly lower if those individuals were included. Only 2 patients had a history of seizures. Two individuals had a different deletion of BP3-BP5, and 1 had a deletion of BP3-BP4. In the family of 1 proband with deletion of BP3-BP4, the deletion was also also present in an unaffected brother, father, and uncle, but not present in a mentally retarded brother, suggesting that it is not of clinical significance. Van Bon et al. 48) concluded that BP4-BP5 deletion does not lead to a clinically recognizable syndrome, but that it likely plays a contributing role in the pathogenesis of conditions affecting the brain, including mental retardation. The variable phenotypic outcome of the deletion is likely to be determined in conjunction with other factors, such as a mechanism for overcoming primary embryologic defects.
Pagnamenta et al. 49) reported 3 male sibs with autism associated with an approximately 2.0-Mb deletion of chromosome 15q13.3 involving BP4-BP5 that was inherited from their unaffected mother. All 3 boys had a history of language delay, and IQ levels ranged from 72 to 96. None had seizures, and none had dysmorphic features, although 2 had an increased head circumference (greater than 97th percentile).
Masurel-Paulet et al. 50) found that 16 (0.35%) of 4,625 patients tested for developmental delay had a microdeletion of chromosome 15q13.3 including the CHRNA7 gene. Twelve patients and 13 relatives had the common deletion between BP4 and BP5 ranging in size from 1.5 to 1.8 Mb. The phenotype was variable, and characterized by mild or no dysmorphic features and mild to moderate mental retardation. Two patients had epilepsy, 6 had anxiety disorder, 3 had phobias, 4 had inhibition, 2 were hyperactive, 1 self-mutilated, and 1 had autistic features. None had schizophrenia. In 6 families, the deletion was inherited from an apparently normal parent, indicating incomplete penetrance; in 4 families, the carrier parent reported learning disabilities. One patient with a severe phenotype including epileptic encephalopathy with retinopathy, autistic features, and choreoathetosis was homozygous for a 1.5-Mb BP4-BP5 deletion. Both of his parents, who carried the deletion, had mild mental retardation. In addition, 3 patients and 2 relatives had a smaller 500-kb deletion. A review of reported cases in the literature indicated that male carriers of a 15q13 deletion are more likely to be symptomatic.
Of 1,035 individuals carrying copy number variants associated with schizophrenia, Sahoo et al. 51) identified 69 individuals with microdeletion at 15q13.3. Indications for study in these 69 individuals included developmental delay, autism, dysmorphic features, seizures, hypotonia, obsessive compulsive disorder, and congenital heart defect. The average age at diagnosis was 6.6 years with an age range of 0.1 to 19.7 years. Sahoo et al. 52) concluded that these and other results from their study, the largest genotype-first analysis of schizophrenia susceptibility loci to that time, suggested that the phenotypic effects of copy number variants associated with schizophrenia are pleiotropic and imply the existence of shared biologic pathways among multiple neurodevelopmental conditions.
Hoppman-Chaney et al. 53) identified 19 individuals, including 10 probands and 9 family members, with a heterozygous deletion of chromosome 15q13.3 including only the CHRNA7 gene and no neighboring genes, and 1 patient with a homozygous deletion of CHRNA7. The patients were ascertained from a database of over 15,000 individuals who underwent cytogenetic testing. Ten individuals were from 2 independent extended families, and the deletion segregated with the phenotype. Among 15 children with the deletion, 5 were under the age of 2 years and did not have obvious neurocognitive problems. The other children had variable developmental delay, cognitive disability, autistic features, and/or attention-deficit hyperactivity disorder. Five of 6 patients with available clinical information had dysmorphic features, such as upslanting palpebral fissures, dental malocclusion, hypertelorism, and macro- or microcephaly. Only 1 patient had seizures. One patient had a de novo deletion, and another with a more severe phenotype had a homozygous deletion. All 5 parents with the deletion had neurocognitive features of the disorder.
Lowther et al. 54) identified a total of 246 cases (133 children, 113 adults) with deletions overlapping or within the 15q13.3 BP4-BP5 region, including 7 novel adult cases from local cohorts. No BP4-BP5 deletions were identified in 23,838 adult controls. Overall, 198 cases (121 children, 77 adults; 80.5%) had at least 1 neuropsychiatric diagnosis. Accounting for ascertainment, developmental disability/intellectual disability was present in 57.7%, epilepsy/seizures in 28.0%, speech problems in 15.9%, autism spectrum disorder in 10.9%, schizophrenia in 10.2%, mood disorder in 10.2%, and attention deficit hyperactivity disorder in 6.5%. By contrast, major congenital malformations, including congenital heart disease (2.4%), were uncommon. Placenta previa occurred in the pregnancies of 4 cases.
Using published and unpublished case subjects as well as clinical microarray data from 38,325 individuals with a range of neurodevelopmental disorders, Uddin et al. 55) identified 156 individuals with 15q13.3 microdeletions impacting the typical BP4-BP5 region. Only 1 individual with this deletion was found among 22,241 control individuals (p less than 1.30 x 10(-29)). Eight of the 156 patients with deletions had a primary diagnosis of autism spectrum disorder (ASD). Analysis of the breakpoints found a minimal region of overlap associated with an atypical smaller deletion in 42 cases, which included only 2 genes: CHRNA7 and OTUD7A. OTUD7A was implicated in particular because a 5-year-old girl had a deletion encompassing only OTUD7A but not CHRNA7, and 3 probands with de novo heterozygous OTUD7A-specific mutations were identified in another cohort of over 6,000 autism spectrum disorder individuals studied.
15q13.3 microdeletion syndrome diagnosis
Individuals with the 15q13.3 microdeletion may have a wide range of clinical manifestations. The deletion itself may not lead to a clinically recognizable syndrome and a subset of persons with the deletion have no obvious clinical findings, implying that penetrance for the deletion is incomplete.
15q13.3 microdeletion should be considered in individuals with the following clinical findings 56):
- Intellectual disability
- Speech delay
- Behavioral problems (poor attention span, hyperactivity, mood disorder, and aggressive and/or impulsive behavior)
Some affected individuals have combinations of these findings, such as intellectual disability and seizures.
Establishing the diagnosis
The diagnosis of the 15q13.3 microdeletion is established by detection of the 2.0-Mb heterozygous microdeletion at chromosome 15q13.3.
The 15q13.3 microdeletion is defined as the presence of a recurrent 2.0-Mb deletion at the approximate position of 30.5-32.5 Mb in the reference genome, which includes deletion of 1.5 Mb of unique sequence as well as an additional 500 kb or more of segmental duplications.
Note: The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from the 15q13.3 microdeletion (see Genetically Related Disorders).
Although several genes of interest (e.g., CHRNA) are within the 2.0-Mb deletion, no single gene has been associated with the disease findings.
Genomic testing methods that determine the copy number of sequences can include chromosomal microarray (CMA) or targeted deletion analysis by fluorescence in situ hybridization (FISH) or multiplex ligation dependent probe amplification (MLPA). Note: The 15q13.3 microdeletion cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques.
- Chromosomal microarray (CMA) using oligonucleotide arrays or SNP genotyping arrays can detect the common deletion in a proband. The ability to size the deletion depends on the type of microarray used and the density of probes in the 15q13.3 region.
- Note: (1) Most individuals with the 15q13.3 microdeletion are identified by CMA performed in the context of developmental delay, intellectual disability, or autism spectrum disorders. (2) Prior to 2008 some CMA platforms did not include coverage for this region and thus may not have detected this deletion.
- Targeted deletion analysis. FISH analysis and MLPA may be used to test at-risk relatives of a proband known to have the 15q13.3 microdeletion.
- Note: (1) Targeted deletion testing by FISH or MLPA is not appropriate for an individual in whom the microdeletion was not detected by CMA designed to target 15q13.3. (2) It is not possible to size the microdeletion routinely by use of FISH or MLPA.
15q13.3 microdeletion syndrome treatment
Ideally treatment is tailored to the specific needs of the individual. Because of the high incidence of neurodevelopmental disability, referral to a clinical psychologist for neuropsychological and/or developmental assessment for treatment recommendations is suggested.
Medical treatment for persons with cardiac defects, epilepsy, autism spectrum disorders, and schizophrenia should follow standard practice for these disorders, considering the age of the patient and the specific manifestations.
Additional management in healthy adults who have the 15q13.3 microdeletion is not necessary, although their medical care providers may benefit from being alerted to the possible increased risk for late-onset manifestations (e.g., schizophrenia).
Close assessment/monitoring of neurocognitive development and developmental milestones are recommended during childhood for all children who have the 15q13.3 microdeletion, with referral to early intervention programs if required.
Medical surveillance for persons with cardiac defects, epilepsy, autism spectrum disorders, and schizophrenia should follow standard practice for these disorders, considering the age of the patient and the specific manifestations.
Agents and circumstances to avoid
About 10% of the individuals with the 15q13.3 microdeletion develop schizophrenia. The use of cannabis has been reported as a risk factor for development of schizophrenia. Although no studies have been performed on the possible additional risk of the use of cannabis by persons with the 15q13.3 microdeletion, discouraging the use of cannabis may be considered.
15q13.3 microdeletion syndrome prognosis
15q13.3 microdeletion prognosis depends on the clinical features. Carriers with learning difficulties in childhood often function normally in adulthood. Survival does not seem to be reduced in the absence of a congenital heart defect 57).
16p11.2 deletion syndrome
16p11.2 deletion syndrome also called AUTS14A, is a disorder caused by a deletion of a small piece of chromosome 16. The deletion occurs near the middle of the chromosome at a location designated p11.2. People with 16p11.2 deletion syndrome usually have developmental delay and intellectual disability 58). Most also have at least some features of autism spectrum disorders. These disorders are characterized by impaired communication and socialization skills, as well as delayed development of speech and language. In 16p11.2 deletion syndrome, expressive language skills (vocabulary and the production of speech) are generally more severely affected than receptive language skills (the ability to understand speech). Some people with this disorder have recurrent seizures (epilepsy).
Some affected individuals have minor physical abnormalities such as low-set ears or partially webbed toes (partial syndactyly). People with this disorder are also at increased risk of obesity compared with the general population. However, there is no particular pattern of physical abnormalities that characterizes 16p11.2 deletion syndrome. Signs and symptoms of the disorder vary even among affected members of the same family. Some people with the deletion have no identified physical, intellectual, or behavioral abnormalities.
Most people tested for the 16p11.2 deletion have come to medical attention as a result of developmental delay or autistic behaviors 59). Other individuals with the 16p11.2 deletion have no associated health or behavioral problems, and so the deletion may never be detected. For this reason, the prevalence of this deletion in the general population is difficult to determine but has been estimated at approximately 3 in 10,000 60).
16p11.2 deletion syndrome causes
People with 16p11.2 deletion syndrome are missing a sequence of about 600,000 DNA building blocks (base pairs), also written as 600 kilobases (kb), at position p11.2 on chromosome 16. This deletion affects one of the two copies of chromosome 16 in each cell. The 600 kb region contains more than 25 genes, and in many cases little is known about their function. Researchers are working to determine how the missing genes contribute to the features of 16p11.2 deletion syndrome.
16p11.2 deletion syndrome inheritance pattern
16p11.2 deletion syndrome is considered to have an autosomal dominant inheritance pattern because a deletion in one copy of chromosome 16 in each cell is sufficient to cause the condition. However, most cases of 16p11.2 deletion syndrome are not inherited. The deletion occurs most often as a random event during the formation of reproductive cells (eggs and sperm) or in early fetal development. Affected people typically have no history of the disorder in their family, although they can pass the condition to their children. Several examples of inherited 16p11.2 deletion have been reported. In inherited cases, other family members may be affected as well.
16p11.2 deletion syndrome symptoms
16p11.2 deletion syndrome is mainly characterized by some degree of developmental delay, intellectual disability, and/or autism spectrum disorder. Developmental delays tend to affect language and cognitive function more than motor function. IQ scores range from mild disability to normal, but those in the normal range typically have other developmental issues such as language delay or autism spectrum disorder 61). Some people with the deletion have no identified issues or abnormalities 62).
Affected people are at increased risk for obesity, and may be at increased risk for seizures and relatively minor heart defects. There is generally not an increased risk for other conditions or medical problems. While people with 16p11.2 deletion syndrome do not have a characteristic pattern of distinctive physical features, several studies have reported various features in affected people 63).
16p11.2 deletion syndrome diagnosis
The 16p11.2 recurrent microdeletion should be suspected in individuals with the following clinical findings:
- Delayed language development (with expressive language typically more affected than receptive language) and abnormal speech articulation
- Learning difficulties/intellectual disability
- Social impairments with or without a diagnosis of autism spectrum disorder (autism spectrum disorder)
- Chiari I/cerebellar tonsillar ectopia
- Vertebral anomalies
- Obesity starting in adolescence, and in the setting of developmental delay
Establishing the diagnosis
The diagnosis of the 16p11.2 recurrent microdeletion is established by demonstration of deletion of the ~593-kb critical region at the approximate position of 29.6-30.2 Mb in the reference genome (GRCh37/hg19).
Of note, an adjacent (distal) recurrent 16p11.2 microdeletion (GRCh37/hg19 chr16:28.8-29.0 Mb) which is also associated with variable features is not discussed further as this GeneReview addresses the 29.6-30.2-Mb recurrent deletion only.
Molecular methods that determine the copy number of sequences can include chromosomal microarray (CMA) or targeted deletion analysis by fluorescence in situ hybridization (FISH). Note: The 16p11.2 microdeletion cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques.
- Chromosomal microarray (CMA) using oligonucleotide arrays or SNP genotyping arrays can detect the recurrent deletion in a proband. The ability to size the deletion depends on the type of microarray used and the density of probes in the 16p11.2 region.
- Note: (1) Most individuals with 16p11.2 recurrent microdeletion are identified by CMA performed in the context of evaluation of developmental delay, intellectual disability, or autism spectrum disorder. (2) Prior to 2008 many CMA platforms did not include coverage for this region and thus may not have detected this deletion.
- Targeted deletion analysis. FISH analysis, quantitative PCR (qPCR), multiplex ligation-dependent probe amplification (MLPA), or other targeted quantitative methods may be used to test relatives of a proband known to have the 16p11.2 recurrent microdeletion.
- Note: (1) Targeted deletion testing is not appropriate for an individual in whom the 16p11.2 recurrent microdeletion was not detected by CMA designed to target this region. (2) It is not possible to size the deletion routinely by use of targeted methods.
16p11.2 deletion syndrome treatment
Treatment should be targeted to the specific deficits identified. Full developmental assessment, including neuropsychological testing by a clinical psychologist, is strongly suggested to establish neurodevelopmental needs and treatment recommendations. Refer to a neurologist if seizures are suspected. Because of the high risk of obesity beginning in adolescence, encourage healthy eating habits with attention to portion size and an active lifestyle from a young age. Routine management of vertebral anomalies.
Routine surveillance, screening, and management based on American Academy of Pediatrics published guidelines on developmental delays and autism spectrum disorder. Maintain a low index of suspicion for possible seizures (which may manifest as, e.g., abnormal movements, staring spells). Obtain brain MRI if manifestations of Chiari I malformation appear. Periodic reevaluation by a medical geneticist to apprise the family of new developments and/or recommendations and facilitate long-term monitoring for emerging medical and/or mental health concerns.
16p11.2 deletion syndrome prognosis
There are no long-term follow-up data for people with 16p11.2 deletion syndrome. The long-term outlook (prognosis) for affected people likely depends on the specific features and severity in each person. Some affected people may have congenital abnormalities such as a heart defect, while others have no identifiable signs or symptoms.
22q11.2 deletion syndrome
22q11.2 deletion syndrome also known by DiGeorge syndrome, velo-cardio-facial syndrome, Cayler cardiofacial syndrome or Sedlackova syndrome, is a disorder caused by the deletion of a small piece of chromosome 22. The deletion occurs near the middle of the chromosome at a location designated q11.2 64).
22q11.2 deletion syndrome has many possible signs and symptoms that can affect almost any part of the body. The features of 22q11.2 deletion syndrome (DiGeorge syndrome) vary widely, even among affected members of the same family. People with 22q11.2 deletion syndrome commonly have heart abnormalities that are often present from birth, recurrent infections caused by problems with the immune system, and distinctive facial features. In affected individuals, the muscles that form the roof of the mouth (palate) may not close completely, even though the tissue covering them does, resulting in a condition called submucosal cleft palate. The abnormal palate is often highly arched and there may be a split in the soft flap of tissue that hangs from the back of the mouth (bifid uvula). Submucosal cleft palate can also interfere with normal speech by causing air to come out of the nose during speech, leading to nasal-sounding speech. Affected individuals may also have breathing problems, kidney abnormalities, low levels of calcium in the blood (which can result in seizures), a decrease in blood platelets (thrombocytopenia), significant feeding difficulties, gastrointestinal problems, and hearing loss. Skeletal differences are possible, including mild short stature and, less frequently, abnormalities of the spinal bones.
Many children with 22q11.2 deletion syndrome have developmental delays, including delayed growth and speech development, and some have mild intellectual disability or learning disabilities. Older affected individuals have difficulty reading, performing tasks involving math, and problem solving. Children with this condition often need help changing and adapting their behaviors when responding to situations. Additionally, affected children are more likely than children without 22q11.2 deletion syndrome to have attention-deficit/hyperactivity disorder (ADHD) and developmental conditions such as autism spectrum disorder that affect communication and social interaction.
Because the signs and symptoms of 22q11.2 deletion syndrome are so varied, different groupings of features were once described as separate conditions. Doctors named these conditions DiGeorge syndrome, velocardiofacial syndrome (also called Shprintzen syndrome), and conotruncal anomaly face syndrome. In addition, some children with the 22q11.2 deletion were diagnosed with the autosomal dominant form of Opitz G/BBB syndrome and Cayler cardiofacial syndrome. Once the genetic basis for these disorders was identified, doctors determined that they were all part of a single syndrome with many possible signs and symptoms. To avoid confusion, this condition is usually called 22q11.2 deletion syndrome, a description based on its underlying genetic cause.
22q11.2 deletion syndrome affects an estimated 1 in 4,000 people 65). However, the condition may actually be more common than this estimate because doctors and researchers suspect it is underdiagnosed due to its variable features. The condition may not be identified in people with mild signs and symptoms, or it may be mistaken for other disorders with overlapping features.
22q11.2 deletion syndrome causes
Most people with 22q11.2 deletion syndrome are missing a sequence of about 3 million DNA building blocks (base pairs) on one copy of chromosome 22 in each cell. This region contains 30 to 40 genes, many of which have not been well characterized. A small percentage of affected individuals have shorter deletions in the same region. This condition is described as a contiguous gene deletion syndrome because it results from the loss of many genes that are close together.
Researchers are working to identify all of the genes that contribute to the features of 22q11.2 deletion syndrome. They have determined that the loss of a particular gene on chromosome 22, TBX1, is probably responsible for many of the syndrome’s characteristic signs (such as heart defects, a cleft palate, distinctive facial features, hearing loss, and low calcium levels). Some studies suggest that a deletion of this gene may contribute to behavioral problems as well. The loss of another gene, COMT, in the same region of chromosome 22 may also help explain the increased risk of behavioral problems and mental illness. The loss of additional genes in the deleted region likely contributes to the varied features of 22q11.2 deletion syndrome.
22q11.2 deletion syndrome inheritance pattern
The inheritance of 22q11.2 deletion syndrome is considered autosomal dominant because a deletion in one copy of chromosome 22 in each cell is sufficient to cause the condition. Most cases of 22q11.2 deletion syndrome are not inherited, however. The deletion occurs most often as a random event during the formation of reproductive cells (eggs or sperm) or in early fetal development. Affected people typically have no history of the disorder in their family, though they can pass the condition to their children. In about 10 percent of cases, a person with this condition inherits the deletion in chromosome 22 from a parent. In inherited cases, other family members may be affected as well.
22q11.2 deletion syndrome symptoms
Signs and symptoms of DiGeorge syndrome (22q11.2 deletion syndrome) can vary in type and severity, depending on what body systems are affected and how severe the defects are. Some signs and symptoms may be apparent at birth, but others may not appear until later in infancy or early childhood.
Signs and symptoms may include some combination of the following:
- Heart murmur and bluish skin due to poor circulation of oxygen-rich blood (cyanosis) as a result of a heart defect
- Frequent infections
- Certain facial features, such as an underdeveloped chin, low-set ears, wide-set eyes or a narrow groove in the upper lip
- A gap in the roof of the mouth (cleft palate) or other problems with the palate
- Delayed growth or growth hormone deficiency
- Difficulty feeding, failure to gain weight or gastrointestinal problems
- Breathing problems
- Poor muscle tone
- Delayed development, such as delays in rolling over, sitting up or other infant milestones
- Delayed speech development or nasal-sounding speech
- Learning delays or disabilities
- Behavior problems.
Additional symptoms may include 66):
- Low levels of calcium (50% of individuals)
- Kidney anomalies (31% of individuals)
- Hearing loss
- Issues with the development of the larynx, trachea, and esophagus (laryngotracheoesophageal anomalies)
- Autoimmune disorders (thrombocytopenia, juvenile rheumatoid arthritis, overactive thyroid)
- Skeletal abnormalities (extra fingers, toes, or ribs, wedge-shaped spinal bones, craniosynostosis)
- Psychiatric illness
- Eye abnormalities (ptosis, coloboma, cataract, and strabismus)
- Central nervous system abnormalities
Individuals may also have an autism spectrum disorders. Psychiatric illness, attention deficit disorder, anxiety, repetitive behaviors, and difficulty with social interactions are also common 67).
22q11.2 deletion syndrome complications
The portions of chromosome 22 deleted in DiGeorge syndrome (22q11.2 deletion syndrome) play a role in the development of a number of body systems. As a result, 22q11.2 deletion syndrome can cause several errors during fetal development. Common problems that occur with 22q11.2 deletion syndrome include:
- Heart defects. 22q11.2 deletion syndrome often causes heart defects that could result in an insufficient supply of oxygen-rich blood. For example, defects may include a hole between the lower chambers of the heart (ventricular septal defect); only one large vessel, rather than two vessels, leading out of the heart (truncus arteriosus); or a combination of four abnormal heart structures (tetralogy of Fallot).
- Hypoparathyroidism. The four parathyroid glands in the neck regulate the levels of calcium and phosphorus in the body. 22q11.2 deletion syndrome can cause smaller than normal parathyroid glands that secrete too little parathyroid hormone (PTH), leading to hypoparathyroidism. This condition results in low levels of calcium and high levels of phosphorus in the blood.
- Thymus gland dysfunction. The thymus gland, located beneath the breastbone, is where T cells — a type of white blood cell — mature. Mature T cells are needed to help fight infections. In children with 22q11.2 deletion syndrome, the thymus gland may be small or missing, resulting in poor immune function and frequent, severe infections.
- Cleft palate. A common condition of 22q11.2 deletion syndrome is a cleft palate — an opening (cleft) in the roof of the mouth (palate) — with or without a cleft lip. Other, less visible abnormalities of the palate that may also be present can make it difficult to swallow or produce certain sounds in speech.
- Distinct facial features. A number of particular facial features may be present in some people with 22q11.2 deletion syndrome. These may include small, low-set ears, short width of eye openings (palpebral fissures), hooded eyes, a relatively long face, an enlarged nose tip (bulbous), or a short or flattened groove in the upper lip.
- Learning, behavioral and mental health problems. 22q11.2 deletion may cause problems with development and function of the brain, resulting in learning, social, developmental or behavioral problems. Delays in toddler speech development and learning difficulties are common. Some children develop attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder. Later in life, the risk of depression, anxiety disorders and other mental health disorders increases.
- Autoimmune disorders. People who had poor immune function as children, due to a small or missing thymus, may also have an increased risk of autoimmune disorders, such as rheumatoid arthritis or Graves’ disease.
- Other problems. A large number of medical conditions may be associated with 22q11.2 deletion syndrome, such as hearing impairment, poor vision, breathing problems, poor kidney function and relatively short stature for one’s family.
22q11.2 deletion syndrome diagnosis
A diagnosis of DiGeorge syndrome (22q11.2 deletion syndrome) is based primarily on a lab test that can detect the deletion in chromosome 22. Your doctor will likely order this test if your child has:
- A combination of medical problems or conditions suggesting 22q11.2 deletion syndrome
- A heart defect, because certain heart defects are commonly associated with 22q11.2 deletion syndrome
In some cases, a child may have a combination of conditions that suggest 22q11.2 deletion syndrome, but the lab test doesn’t indicate a deletion in chromosome 22. Although these cases present a diagnostic challenge, the coordination of care to address all of the medical, developmental or behavioral problems will likely be similar.
22q11.2 deletion syndrome treatment
Although there is no cure for DiGeorge syndrome (22q11.2 deletion syndrome), treatments can usually correct critical problems, such as a heart defect or cleft palate. Other health issues and developmental, mental health or behavioral problems can be addressed or monitored as needed.
Treatments and therapy for 22q11.2 deletion syndrome may include interventions for:
- Hypoparathyroidism. Hypoparathyroidism can usually be managed with calcium supplements and vitamin D supplements.
- Heart defects. Most heart defects associated with 22q11.2 deletion syndrome require surgery soon after birth to repair the heart and improve the supply of oxygen-rich blood.
- Limited thymus gland function. If your child has some thymic function, infections may be frequent, but not necessarily severe. These infections — usually colds and ear infections — are generally treated as they would be in any child. Most children with limited thymic function follow the normal schedule of vaccines. For most children with moderate thymus impairment, immune system function improves with age.
- Severe thymus dysfunction. If the impairment of the thymus is severe or there’s no thymus, your child is at risk of a number of severe infections. Treatment requires a transplant of thymus tissue, specialized cells from bone marrow or specialized disease-fighting blood cells.
- Cleft palate. A cleft palate or other abnormalities of the palate and lip can usually be surgically repaired.
- Overall development. Your child will likely benefit from a range of therapies, including speech therapy, occupational therapy and developmental therapy. In the United States, early intervention programs providing these types of therapy are usually available through a state or county health department.
- Mental health care. Treatment may be recommended if your child is later diagnosed with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, depression, or other mental health or behavioral disorders.
- Management of other conditions. These may include addressing feeding and growth issues, hearing or vision problems, and other medical conditions.
Prevention of secondary complications
Immunization of infants who have lymphocyte abnormalities with live vaccines is not recommended; reevaluate immune status in childhood before giving live vaccines; antibody studies to assess results of immunizations are warranted; irradiated blood products are recommended until normalization of the immune system can be confirmed; serum ionized calcium concentration should be measured pre- and postoperatively to avoid hypocalcemic seizures; consider assessment of carotid arteries prior to surgical procedures involving the pharynx; consider possible effects on speech prior to adenoidectomy; consider assessment of cervical spine anomalies prior to hyperextension of the neck during surgical procedures/athletic pursuits; consider pre- and postoperative sleep studies when performing pharyngeal procedures; consider assessment of platelet volume and function prior to surgical procedures.
Follow up as needed on a “system by system” basis, but including routine reassessment of serum ionized calcium and thyroid studies; reevaluation of immunologic status prior to live virus vaccines; annual complete blood count and differential; ophthalmologic evaluation prior to school age; evaluation of nasal speech quality; audiology evaluation prior to school enrollment; surveillance for scoliosis; routine dental care; regular speech, language and developmental assessments to provide appropriate remediation.
Agents and circumstances to avoid
Carbonated drinks and alcohol consumption may exacerbate hypocalcemia. Caffeine intake may contribute to or worsen anxiety.
Health care team
Because 22q11.2 deletion syndrome can result in so many problems, several specialists will likely be involved in diagnosing specific conditions, recommending treatments and providing care. This team will evolve as your child’s needs change. Specialists on your care team may include these professionals and others, as needed:
- Children’s health specialist (pediatrician)
- Expert in inherited disorders (geneticist)
- Heart specialist (cardiologist)
- Immune system specialist (immunologist)
- Ear, nose and throat (ENT) specialist
- Infectious disease specialist
- Hormone disorder specialist (endocrinologist)
- Surgeon who specializes in correcting such conditions as a cleft palate (oral and maxillofacial surgeon)
- Surgeon who specializes in correcting heart defects (cardiovascular surgeon)
- Occupational therapist to help develop practical, everyday skills
- Speech therapist to help improve verbal skills and articulation
- Developmental therapist to help develop age-appropriate behaviors, social skills and interpersonal skills
- Mental health professional, such as a pediatric psychiatrist or psychologist
22q11.2 deletion syndrome prognosis
There is a wide range of symptoms and severity among people with 22q11.2 deletion syndrome. The long-term outlook for each person depends on the specific signs and symptoms each individual has.
Factors that may impact the severity of the disease and the likelihood for a shortened lifespan include whether or not a congenital heart defect is present and how severe the defect is, as well as the severity of immune system problems. For instance, individuals with complete absence of the thymus gland and absent T cells may pass away prematurely 68).
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