Trisomy Disorders

Archive for October 2008

Distal Trisomy 10q

What is Distal Trisomy 10q? Distal Trisomy 10q is an extremely rare syndrome in which a person has an extra end (distal) portion of chromosome 10, specifically from the long arm (q). This can occur spontaneously at conception (de novo), or most commonly, from a translocation in one of the parents. In the latter case, one of the parents has the tails of chromosome 10 and another chromosome swapped. The parent has a full set of genes, but when the child gains one half of these chromosomes from the affected parent, the child ends up with an unbalanced set of genes. The effect on the child can vary from mild to very severe and is related to how many extra genes are present from 10q. Additionally, in translocation cases, there are generally missing genes from the complimentary chromosome of the translocation. See the images of chromosome 10q.

For more information:

Distal Trisomy 10q Families

Trisomy Listserv

Other readings:

Distal trisomy 10q/partial monosomy 14q: an unusual clinical picture.

Distal trisomy 10q and limb defects

Distal 10q trisomy associated with bilateral hydronephrosis in infancy

Distal trisomy of 10q. Report of a new case of duplication 10q25.2-25.3–>qter defined by FISH


The diagnostic utility of a genetics evaluation in children with pervasive developmental disorders

January 8, 2006


Abdul-Rahman OA, Hudgins L.

Division of Medical Genetics, Department of Pediatrics, Stanford University, 300 Pasteur Drive, H-315, Stanford, CA 94305, USA.


 A genetics evaluation of children with pervasive developmental disorders (PDDs) identifies a diagnosis in 6% to 15% of cases. However, previous studies have not measured the incidence of genetic disorders among children with autistic-like features who do not necessarily meet the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition criteria for PDD.


We identified 101 patients at our institution referred for PDD, autism, Asperger syndrome, or autistic features. Seventy-eight were males and 23 were females, giving a male-to-female ratio of 3.4:1. No diagnosis was identified on examination alone, although Rett syndrome was suspected in six females. Seventeen patients did not undergo any type of testing because of noncompliance.


Of the remaining 84 patients analyzed, seven (8.3%) were found to have abnormalities on testing. Three chromosomal anomalies were found: one with 5p duplication, one with low-level mosaicism for trisomy 21, and one with an unbalanced 10;22 translocation. Three females were diagnosed with Rett syndrome after MECP2 analysis identified a disease-causing mutation. The remaining patient was found to have an elevated urine orotic acid, with a normal ammonia level, of unknown significance.


On the basis of our series, the yield of a genetics evaluation in patients with featuresof PDD who do not necessarily meet the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition criteria is 8.3%. Approximately half of these were the result of a chromosomal abnormality. Three cases of Rett syndrome were identified for which autistic behaviors are a well-described feature. These findings suggest that a high-resolution karyotype provides the greatest diagnostic yield for patients with autistic-like features. MECP2 analysis should be considered for females who present with autistic behaviors.

PMID: 16418599 [PubMed – in process]

Genotype-Phenotype CorrelationsAlthough the size of the deletion in 22q13.3 syndrome ranges from 100 kb to more than 9 Mb, Wilson et al (2003) found that deletion size showed little correlation with the clinical features of this disorder. Their analysis of 56 individuals with deletions ranging from 130 kb to more than 9 Mb revealed that all individuals showed the characteristic neurological features of developmental delay and absent or delayed speech. While all other individuals in the study showed moderate-to-profound mental retardation, the individual with the smallest (130 kb) deletion exhibited milder delays, less severe speech delay, and few of the typical dysmorphic features [Flint et al 1995 , Wong et al 1997]. In a report by Anderlid et al (2002), a 30-year-old woman with a 100-kb deletion of 22q13 also showed mild mental retardation and speech delay with minor dysmorphic features consistent with 22q13.3 syndrome. With increasing age, she experienced a decline in speech, onset of abnormal behavior with autistic features, and deterioration of daily living skills.For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.Evaluations at Initial DiagnosisGenetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.kphelan@mplnet.comChromosome 22 Central
237 Kent Avenue
Timmins, ON
Canada P4N 3C2
Phone: 705-268-3099
Email:….Chromosome Deletion Outreach, Inc
PO Box 724
Boca Raton, FL 33429-0724
Phone: 888-CDO-6880 (888-236-6680); 561-395-4252 (family helpline)
Email:….National Information Center for Children and Youth with Disabilities (NICHCY)
P.O Box 1492
Washington, CD 20013
Phone: 800-695-0285
see complete article and references:



Features of 22q13.3 syndrome are apparent in all individuals with deletion 22q13.3 in a significant proportion of cells.


No true synonyms exist for 22q13.3 deletion, but some have used the term Phelan-McDermid syndrome after the individuals who originally described the disorder.


The prevalence of deletion 22q13.3 is unknown. Deletion 22q13.3 remains underdiagnosed due to the failure to detect the deletion of chromosome 22 in routine chromosome studies and the failure to recognize the phenotype on clinical examination. In surveys of subtelomeric deletions, deletion of 22q13.3 is the second most common deletion, after deletion 1p36.3 [Heilstedt et al 2003].

Differential Diagnosis


Ring chromosome 22. Ring chromosomes are usually accompanied by the loss of genetic material from the distal long (q) arm and distal short (p) arm. For ring chromosome 22, loss of shortarm and satellite material is of no clinical significance. In individuals with ring chromosome 22, the size of the deleted segment of 22q determines the phenotype, which ranges from normal to severely affected. Phenotypic expression may further be complicated by instability of the ring chromosome 22 during mitosis, which may cause the chromosome to become broken, lost, or duplicated.

Regardless of which autosome is involved, the general phenotype of the “ring chromosome syndrome” includes growth retardation, cognitive impairment, and minor dysmorphic features. Individuals with ring chromosome 22 often show features similar to 22q13.3 syndrome: global developmental delay, severe speech deficit, hypotonia, and minor dysmorphic features. Unlike 22q13.3 syndrome, ring chromosome 22 is characterized by delayed growth (20-24% of individuals) and microcephaly (33% of individuals) [Ishmael et al 2003 , Luciani et al 2003].

Ring chromosomes are difficult to characterize cytogenetically; molecular characterization is complicated by instability of the ring. Nonetheless it is reasonable to assume that individuals who are missing 22q13.3 would have the phenotype of 22q13.3 syndrome. Many families with ring chromosome 22 are members of the Phelan-McDermid Syndrome/Deletion 22q13.3 Syndrome Foundation.

Other disorders. 22q13.3 syndrome should be suspected in any infant with neonatal hypotonia of unknown etiology. As in Prader-Willi syndrome , neonatal hypotonia and feeding difficulty can be the earliest presenting symptoms. Any neonate referred for chromosome analysis, FISH, or molecular studies to rule out Prader-Willi syndrome should also be tested for 22q13.3 syndrome.

The diagnosis of 22q13.3 syndrome should also be suspected in individuals with “atypical” Angelman syndrome . Features common to both 22q13.3 syndrome and Angelman syndrome include global developmental delay, absent speech, unsteady gait, and minor dysmorphic features. De Vries et al (2002) evaluated 44 individuals with features of Angelman syndrome but without the characteristic chromosome 15 abnormality and found no evidence of deletion 22q13.3. In the study group, 73% of individuals had severe developmental delay, 77% had serious speech impairment, and almost 50% had microcephaly. The failure to find deletion of 22q13.3 was not surprising since the features of the study group were not highly suggestive of 22q13.3 syndrome, in which global developmental delay and absent or severely delayed speech are present in over 95% of individuals and microcephaly is found in fewer than 10%.

Other chromosomal and non-chromosomal diagnoses have been applied to individuals prior to the diagnosis of 22q13.3 syndrome. These diagnoses include velocardiofacial syndrome (see 22q11.2 Deletion Syndrome), Williams syndrome , trichorhinophalangeal syndrome, Smith-Magenis syndrome , fragile X syndrome , F-G syndrome, cerebral palsy, spastic paraplegia (see Hereditary Spastic Paraplegia Overview), and autism (See Autism Overview).



Upon initial diagnosis, the following evaluations should be performed to identify findings of 22q13.3 syndrome:

A complete physical and neurological examination
Determination of head circumference, height, weight, and other anthropometric measurements

A family history to determine if any relatives are similarly affected

A medical history, focusing on feeding problems, increased incidence of infection, evidence of kidney malfunction and/or gastroesophageal reflux, and symptoms of increased intracranial pressure

Renal ultrasound examination to evaluate for ureteral reflux, dysplastic kidney, multicystic kidneys, and other renal problems
Brain imaging studies (MRI, CAT scan) in individuals with microcephaly and in individuals with symptoms suggestive of increased intracranial pressure from arachnoid cysts, including irritability, incessant crying, severe headache, cyclic vomiting, and seizures

Multidisciplinary developmental evaluation to assess motor, cognitive, social, and vocational skills

Comprehensive speech/language evaluation including an audiological examination

A medical genetics consultation to discuss clinical manifestations, prognosis, natural history, therapies, and recurrence risks

Treatment of Manifestations

Neurologic consultation for neonatal hypotonia

Evaluation of feeding problems (usually consisting of swallowing or sucking difficulties) by a feeding specialist and/or occupational therapist and speech pathologist

Evaluation by a child development specialist if autistic-like features are present. Medication to reduce hyperactivity, anxiety, and self-stimulatory behavior can be helpful in some individuals.

An EEG in individuals with seizures to help determine the appropriate antiepileptic drugs (AEDs). An EEG may also be used to detect subclinical seizure activity.

Ocular examination in individuals with strabismus or other indications of visual impairment. Assessment of cortical visual impairment by a team including physical therapists, occupational therapists, orientation and mobility specialists, pediatric neurologists, and pediatric ophthalmologists.

Regular dental evaluations, routine brushing, and fluoride. Oral-motor therapy may alleviate chewing and swallowing problems. A pediatric orthodontist should be consulted to monitor malocclusion and determine if orthodontic therapy is required.

A sleep study to evaluate for sleep apnea if sleep disturbance is present. Sleep apnea should be treated by routine protocols. If sleep apnea is not the cause of sleep disturbance, a bedtime routine to calm and soothe the child should be established.

Treatment with typanostomy tubes for recurrent ear infections. If hearing deficits are suspected because of recurrent ear infections and lack of expressive speech, hearing should be evaluated by a specialist who is experienced in testing severely delayed children. If hearing is impaired, management with hearing aids should be considered.

Treatment for cardiac, renal, respiratory, immunologic and other medical issues by standard protocols

Surgical removal of ingrown toenails to prevent infection
Use of pressure stockings, elevating the foot of the bed for treatment of lymphedema

Early intervention programs, intensive physical and occupational therapies, adaptive exercise and sports programs, and other therapies to improve coordination and strengthen muscles
Walkers or other assistive devices to aid in walking by ameliorating balance problems

Therapies to improve verbal and nonverbal communication because perceptive language is often more advanced than expressive language. Sign language, picture exchange systems, and computer touch screens may augment communication.

Nutritional assessment for individuals with persistent symptoms of gastroesophageal reflux (GER) or cyclic vomiting. In infants, GER may be treated by thickening formula, smaller feedings, and positioning. Older children should avoid spicy food and food than may cause irritation and should refrain from eating within two to three hours of bed time. In some cases, medication is required to control GER. In the most persistent cases, surgery (fundoplication) may be required.

Intravenous fluids to prevent dehydration in individuals with recurrent vomiting. A neurological evaluation is indicated to assess cyclic vomiting, particularly to address issues of increased intracranial pressure. If increased intracranial pressure is caused by an arachnoid cyst, surgery may be warranted.
Vigilance in monitoring children, particularly those who can walk or run independently, by the parents or caregivers; children may be impulsive and are not aware of the consequences of their behavior.


Ongoing pediatric care with regular immunizations
Evaluation by a neurologist for changes in behavior or regression of skills
Agents/Circumstances to Avoid

Exposure to high temperatures and extended periods in the sun should be avoided. Individuals with deletion 22q13.3 do not perspire normally and tend to overheat easily.

Therapies Under Investigation
Search for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling


Mode of Inheritance

22q13.3 deletion syndrome can be the result of a de novo or of an inherited chromosome abnormality.

Risk to Family Members
Parents of a proband

Most probands have a de novo chromosome deletion and their parents have normal karyotypes. Familial chromosome rearrangements have been identified in 15 to 20% of probands.
The majority of simple deletions of 22q13.3 (69-74%) occur on the paternal chromosome 22 [Luciani et al 2003 , Wilson et al 2003].
About 80% of the derivative chromosomes involving 22q13.3 are the result of familial translocations. Various parental chromosome rearrangements, including an insertional translocation, a pericentric inversion, and mosaicism have been observed [Watt et al 1985 ; Slavotinek et al 1997 ; Phelan, unpublished data].
Parents of a proband with a structurally unbalanced chromosome constitution (e.g., deletion or translocation) are at risk of having a balanced chromosome rearrangement.
Targeted chromosome analysis and FISH studies are warranted in parents of individuals with deletion 22q13.3.
FISH studies should include the examination of a sufficient number of cells to rule out mosaicism in a parent.
Sibs of a proband

The risk to sibs of a proband with 22q13.3 deletion syndrome depends upon the chromosome findings in the parents.
As with other de novo chromosome rearrangements, the recurrence risk for future pregnancies is negligible when parental karyotypes are normal.
If a parent has a balanced structural chromosome rearrangement, the risk to sibs is increased and is dependent upon the specific chromosome rearrangement and the possibility of other variables.
Because all phenotypically normal parents of probands have not been evaluated for mosaicism, the incidence of parental mosaicism is unknown. Based on data from 200 families, the finding of two sibs born to a parent who is mosaic for deletion 22q13.3 suggests that the risk to sibs of a proband is less than 0.5% [Phelan, unpublished data].
The occurrence of germline mosaicism has not been reported in deletion 22q13.3, although the possibility cannot be excluded.
Offspring of a proband. No individuals diagnosed with 22q13.3 syndrome have been known to reproduce.

Other family members. The risk to other family members depends upon the status of the proband’s parents. If a parent is found to have a balanced chromosome rearrangement, his or her family members may be at risk and should be offered chromosome analysis and FISH.

Carrier Detection
If a parent of the proband is found to have a balanced chromosome rearrangement, at-risk family members can be tested by chromosome analysis and/or FISH.

Related Genetic Counseling Issues
Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

Prenatal Testing
Prenatal diagnosis for pregnancies at increased risk is possible by chromosome analysis and/or FISH of fetal cells obtained by amniocentesis usually performed at about 15-18 weeks’ gestation or by chorionic villus sampling (CVS) at about 10-12 weeks’ gestation. Both mosaic and non-mosaic deletions of 22q13.3 have been successfully identified prenatally [Riegel et al 2000 , Phelan 2001 , Phelan et al 2001].

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Molecular Genetics

Molecular Genetics of 22q13.3 Deletion Syndrome Gene Symbol

Chromosomal Locus Protein Name
Unknown 22q13.3 Unknown

Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.

OMIM Entries for 22q13.3 Deletion Syndrome


Molecular Genetic Pathogenesis

The minimum region of overlap of deletions leading to 22q13.3 syndrome is a 100-kb region delineated proximally by cosmid n85a3 and distally by cosmid n1g3. The cosmid clone n85a3 is distal to the ARSA locus and overlaps the 3′ half of SHANK3 (PROSAP2), the candidate gene for the neurological deficits (developmental delay and absent speech) in 22q13.3 syndrome [Anderlid et al 2002]. SHANK3 belongs to a family of proteins that interacts with receptors of the post-synaptic membrane. These multidomain proteins are important scaffolding molecules in the post-synaptic density (PSD) and function to receive and integrate synaptic signals and transduce them into post-synaptic cells. In addition to their role in the assembly of the PSD during synaptogenesis, the SHANK proteins may play a role in synaptic plasticity and in the regulation of dendritic spine morphology [Boeckers et al 2002]. SHANK3 is plausible as the candidate gene in 22q13.3 syndrome because it is located in the critical region, it is preferentially expressed in the cerebral cortex and the cerebellum, and it encodes a protein in the PSD of excitatory synapses[Luciani et al 2003 , Wilson et al 2003]. Disruption of SHANK3 resulting in features of 22q13.3 syndrome was first reported by Bonaglia et al (2001) in a child with a de novo balanced translocation t(12;22) (q24.1;q13.3). Subsequently, Anderlid et al (2002) described the disruption of SHANK3 resulting from a 100-kb deletion in a patient with the phenotype of 22q13.3 deletion syndrome.



Phelan-McDermid Syndrome/22q13 Deletion Syndrome Foundation
250 East Broadway
Maryville, TN 37804
Phone: 800-932-2943
Fax: 865-380-9191








….Terminal 22q deletion syndrome: a newly recognized cause of speech and language disability in the autism spectrum

Related Articles


Pediatrics, August, 2004

Phelan-McDermid Syndrome – 22q13 deletion – Page One

Author: Katy Phelan, PhD, FACMG

Posted: 11 May 2005


Disease characteristics. Deletion 22q13.3 is a microdeletion syndrome in which the affected individuals have neonatal hypotonia, normal to accelerated growth, absent to severely delayed speech, global developmental delay, and minor dysmorphic facial features. Other features include large, fleshy hands, dysplastic toenails, sacral dimple, and decreased perspiration. Behavior characteristics include mouthing or chewing non-food items, increased tolerance to pain, and autistic-like affect.

Diagnosis/testing. The diagnosis of 22q13.3 syndrome is confirmed by demonstration of a deletion or disruption of 22q13.3; approximately 75% of individuals have “simple” deletions, either terminal or interstitial, and about 25% have deletions resulting from an unbalanced translocation or other structural rearrangement. Many 22q13.3 simple deletions can be detected by routine chromosome analysis at the 500-550 band level (and confirmed by FISH studies), but high-resolution analysis may not detect subtle deletions. The minimum region of overlap of deletions leading to 22q13.3 syndrome is a 100-kb region delineated proximally by cosmid n85a3 and distally by cosmid n1g3. The cosmid clone n85a3 is distal to the ARSA locus and overlaps the 3′ half of SHANK3 (PROSAP2), the candidate gene for neurological deficits in 22q13.3 syndrome. Commercially available FISH probes for detecting deletion of 22q13 include the ARSA probe and subtelomere probes; the combined use of these probes detects nearly 100% of deletions resulting in 22q13.3 deletion syndrome.

Management. Management of 22q13.3 deletion syndrome includes neurologic consultation for neonatal hypotonia; oral-motor therapy to alleviate chewing and swallowing problems and orthodontic therapy for malocclusion; medication to reduce hyperactivity, anxiety, and self-stimulatory behavior; antiepileptic drugs for individuals with seizures; treatment with typanostomy tubes for recurrent ear infection; treatment for visual impairment and cardiac, renal, respiratory, immunologic, and other medical issues by standard protocols; removal of ingrown toenails to prevent infection; pressure stockings to treat lymphedema; physical and occupational therapies and exercise programs to improve coordination and strengthen muscles; augmentation of communication with sign language, picture exchange systems, and computer touch screens; and treatment of gastroesophageal reflux by thickening of formula, smaller feedings, and positioning in infants and avoidance of spicy or irritating foods in older children. Individuals should avoid exposure to high temperatures and extended periods in the sun as they do not perspire normally.

Genetic counseling. 22q13.3 deletion syndrome can be the result of a de novo chromosome deletion or of an inherited chromosome abnormality. Most probands have a de novo chromosome deletion; familial chromosome rearrangements have been identified in 15-20% of probands. Prenatal testing by chromosome analysis and/or FISH for pregnancies at increased risk is available clinically.


Deletion 22q13.3 is a microdeletion syndrome suspected in children with the following:
Neonatal hypotonia
Normal to accelerated growth
Absent to severely delayed speech
Global developmental delay
Normal head circumference
Minor dysmorphic facial features including:
Full brow
Flat midface
Puffy eyelids
Long eyelashes
Wide nasal bridge
Puffy cheeks
Pointed chin
Large or prominent ears

Other features that raise suspicion of 22q13.3 include relatively large and fleshy hands, dysplastic toenails, sacral dimple, and decreased perspiration. Behavior characteristics include mouthing or chewing non-food items, increased tolerance to pain, and autistic-like affect.


Cytogenetic Testing
The diagnosis of 22q13.3 syndrome is confirmed by demonstration of a deletion or disruption of 22q13.3.

Approximately 75% of individuals have “simple” deletions which are either:

A “terminal” deletion: A single break in the chromosome arm with loss of the segment distal to the break
An “interstitial” deletion: Two breaks within the same chromosome arm and loss of the intervening segment

Approximately 25% of individuals have deletions resulting from an unbalanced translocation or other structural rearrangement. Unbalanced translocations are characterized by deletion of 22q13.3 and partial trisomy of a second chromosomal segment.

Note: Although many 22q13.3 simple deletions can be detected by routine chromosome analysis (500-550 band level), even high resolution analysis (>550 bands) may fail to detect subtle deletions. In over 30% of affected individuals, two or more G-banded chromosome studies are performed to detect this deletion [Phelan, personal observation]. Indications that led to repeat chromosome studies that revealed deletion 22q13 included:

Postnatal findings of hypotonia, failure to thrive, and/or dysmorphic features in infants who had had normal prenatal cytogenetic studies.
Band resolution of the first study inadequate to detect subtle rearrangements.
High-resolution analysis targeted to examine a specific chromosome based on clinical findings.
High clinical suspicion of a chromosomal disorder leading to repeated chromosome analyses, often accompanied by sub-telomere FISH studies.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by at least one US CLIA-certified laboratory or a clinical laboratory outside the US. GeneTests does not independently verify information provided by laboratories and does not warrant any aspect of a laboratory’s work; listing in GeneTests does not imply that laboratories are in compliance with accreditation, licensure, or patent laws. Clinicians must communicate directly with the laboratories to verify information. —ED.

Gene. The minimum region of overlap of deletions leading to 22q13.3 syndrome is a 100-kb region delineated proximally by cosmid n85a3 and distally by cosmid n1g3. The cosmid clone n85a3 is distal to the ARSA locus and overlaps the 3′ half of SHANK3 (PROSAP2), the candidate gene for the neurological deficits (developmental delay and absent speech) in 22q13.3 syndrome.

Molecular genetic testing: Clinical uses

Prenatal diagnosis

Molecular genetic testing: Clinical method

Fluorescence in situ hybridization (FISH). The commercially available FISH probes for detecting deletion of 22q13 include the arylsulfatase A (ARSA) probe and subtelomere probes. One of the commonly used ARSA probes is 310 kb in size and maps to 22q13.33 [Vysis, Downers Grove, IL, Part # 32-190012]. The subtelomere probe (D22S1726) is 80 kb in size and is estimated to be within 300 kb of the end of chromosome 22 [Vysis, Downers Grove, IL, Part #33-27000]. The combined use of the probes for ARSA and for the subtelomere region should detect 100% of the deletions resulting in this syndrome.

Deletion 22q13.3 observed on routine cytogenetic studies should be confirmed with FISH studies.

Although deletion of ARSA is seen in the majority of individuals with deletion 22q13.3, FISH analysis for ARSA may fail to identify more distal deletions involving the telomeric region.

22q subtelomeric probes detect deletions more distal to ARSA but could miss interstitial deletions [Flint et al 1995].

Note: 1) Commercially available probe sets designed for detection of deletion 22q11.2 (Velocardiofacial/DiGeorge syndrome) typically use the ARSA gene as the control probe. 2) If clinical suspicion of 22q13.3 syndrome is strong and if the deletion is not demonstrated by the initial cytogenetic analysis, probes for ARSA and for the subtelomere region of 22q should be used sequentially.

Molecular genetic testing: Research. Although polymorphisms exist within SHANK3, no clinically significant mutations have been identified [McDermid, personal communication].

Table 1. Molecular Genetic Testing Used in 22q13.3 Deletion Syndrome

Test Method Mutations Detected Mutation Detection Rate Test Availability

FISH Deletion 22q13.3 ~100% when both ARSA and subtelmorere 22q probes are used Clinical

Testing Strategy for a Proband

Cytogenetic analysis at or above the 550-band level should be performed to determine if an obvious cytogenetic abnormality is present.

If deletion 22q13.3 is suspected, FISH testing should accompany cytogenetic analysis.

Even if previous chromosome studies have been reported as normal, repeat chromosome studies (with FISH for ARSA and/or the 22q subtelomere) are indicated when clinical suspicion of 22q13.3 syndrome is strong.

Genetically Related Disorders
No other known phenotypes are associated with deletion 22q13.3.

Clinical Description

Natural History

Males and females are equally affected with no apparent parent-of-origin effect.

Table 2. Features of Deletion 22q13.3 Syndrome Prevalence Features

>95% Neonatal hypotonia
Global developmental delay
Absent or severely delayed speech
Normal to accelerated growth


>75% Large, fleshy hands
Dysplastic toenails
Long eyelashes
Increased tolerance to pain
Mouthing/chewing/tooth grinding


>50% Dolichocephaly
Prominent or large ears
Full brow
Full or puffy cheeks
Full or puffy eyelids
Deep-set eyes
Flat midface
Wide nasal bridge
Bulbous nose
Pointed chin
Sacral dimple
Decreased perspiration with tendency to overheat


>25% Strabismus
Renal problems
GE reflux
Malocclusion/wide spaced teeth
Epicanthal folds
Long philtrum
High arched palate


Hypotonia. Newborns with deletion 22q13.3 have generalized hypotonia that may be associated with weak cry, poor head control, and feeding difficulties leading to failure to thrive. Head size is typically within normal range with microcephaly reported in fewer than 5% of individuals.

Developmental delay. Most affected individuals have moderate-to-profound developmental delay, although a few individuals with small subtelomeric deletions are reported to have mild delays. Major milestones are delayed: the average age for rolling over is about eight months, for crawling about 16 months, and for walking about three years. Poor muscle tone, lack of balance, and decreased upper body strength contribute to the delay in walking. Gait is typically broad-based and unsteady. Toilet training is difficult to achieve and requires extreme vigilance by parents and caregivers. Children may stay dry at night but become wet or soiled during the day because they are unable to communicate their needs.

Speech delay. Infants typically babble at the appropriate age and children may acquire a limited vocabulary. However, by about four years of age many children lose their ability to speak. With intense occupational, speech, and physical therapy they may regain speech and increase their vocabularies. Although speech remains impaired throughout life, individuals can learn tocommunicate with the aid of aggressive therapy and communication training. Receptive communications skills are more advanced than expressive language skills as demonstrated by the ability of affected children to follow simple commands, demonstrate humor, and express emotions.

Individuals with 22q13.3 syndrome have a delayed response to verbal cues. They also have difficulty discerning spoken words from background noise. These two factors, along with the frequent occurrence of ear infections, contribute to the perception that hearing may be impaired. In fact, over 80% of affected individuals have normal hearing.

Growth manifestations. Intrauterine growth in deletion 22q13.3 syndrome is appropriate for gestational age; the mean gestational age is 38.2 weeks. Postnatal growth is normal or accelerated. Height is advanced for age, but weight is not increased so that children appear tall and thin. The hands appear large and fleshy. Toenails are often dysplastic, thin, and flaky and tend to become ingrown. Fingernails are usually normal.

Atypical behavior. Behavior may be autistic-like with poor eye contact, stereotypic movements, and self-stimulation. Other abnormal behaviors include habitual chewing or mouthing, tooth grinding, increased tolerance to pain, and sleep disturbance. Affected individuals may have difficulty falling asleep and staying asleep, although sleep apnea is not a problem. Affected individuals may become agitated in unfamiliar, noisy, or crowded surroundings. As a result of high pain tolerance and lack of expressive communication skills, affected individuals may suffer cuts, scrapes, or even broken bones without indicating that they are in pain. Individuals may suffer ear infections, GE reflux, increased intracranial pressure, or other painful medical conditions without indicating discomfort. Aggressive behavior such as biting, hair pulling, or pinching is seen in about 25% of affected individuals.

Vision impairment. Most affected individuals have normal vision although hyperopia and myopia are observed. Cortical visual impairment, characterized by extensive use of peripheral vision, difficulty in processing cluttered images, problems with depth perception, and the tendency to look away from objects before reaching for them, has been reported in about 6% of affected individuals. The quality of vision fluctuates, being better at some times than others. Blindness and optic nerve hypoplasia have been associated with cortical visual impairment.

Renal function. Renal function is typically normal although frequent urinary tract infections, cystic kidneys, dysplastic kidney, hydronephrosis, and vesico-ureteral reflux have been reported.

Gastrointestional findings. Gastroesophageal reflux is seen in about 30% and cyclic vomiting in about 25% of individuals.

Dental malocclusion. The most frequently encountered dental problems are malocclusion and crowding. Poor muscle tone, incessant chewing, tooth grinding, and tongue thrusting may contribute to malocclusion. Malocclusion may be accompanied by difficulty swallowing and drooling, and may contribute to difficulties in verbalization.

Neurologic manifestations. Arachnoid cysts occur in about 15% of individuals compared to about 1% in the general population. Other neurological problems include reduced myelination, frontal lobe hypoplasia, agenesis of the corpus callosum, ventriculomegaly, and seizures. Many seizures are febrile and do not require medication; however, grand mal seizures, focal seizures, and absence seizures have been described. No characteristic EEG findings are associated with deletion 22q13.3.

Lymphedema. Both lymphedema and recurrent cellulitis have been observed in about 10% of individuals, typically becoming problematic during the teenage and adult years.

Fertility. No individuals diagnosed with 22q13.3 syndrome have been known to reproduce. Nonetheless, no fertility studies have been performed that would exclude the possibility of reproduction. Females with deletion 22q13.3 go through puberty and begin their menstrual periods at the normal age.

Life span impact. Longitudinal data are insufficient to determine life expectancy. However, life-threatening or life-shortening cardiac, pulmonary, or other organ system defects are not common. The paucity of older adults with 22q13.3 syndrome reflects the difficulty in establishing this diagnosis prior to the advent of high-resolution chromosome analysis and FISH.

Mosaic deletion 22q13.3. Thephenotypically normal mother of two affected children was mosaic for deletion 22q13.3, resulting from an unbalanced translocation with the satellite region of an unidentified acrocentric chromosome. The derivative chromosome 22 was observed in 6% of cells from maternal peripheral blood [Phelan, unpublished data].

This condition was first identified by Dr. Harry Klinefelter at the Massachusetts General Hospital in Boston.  A report published he and his coworkers reported case studies on nine men who had enlarged breasts, sparse facial and body hair and an inability to produce sperm.


Now more appropriately referred to as XXY Male of XXY Male Syndrome, males born with this condition have an extra sex chromosome XXY instead of the usual  genotype XY.  It is associated with a 47XXY karyotype and statistically occurs in 1/500 newborns.

Clinical features

 Klinefelter is occasionally associated with lymphatic blockage or fetal hydrops and thus is included in a discussion of developmental disorders of the lymphatics.

Original symptoms included tall stature, long upper extremities, poor pubertal development, microorchidism, enlarged breasts, sparce facial and body hair, small testes and subsequent sterility.

Recent studies have expanded the original symptoms to include infertility, incomplete masculinization; feminine, or pear shaped, body and body hair distribution, decreased libido,  osteoporosis,  taurodontism, venous disease (which may include mitral valve prolapse, varicose veins and venous ulcers),  learning and emotional disorders, autoimmune disorders,  low energy and self esteem,  communication difficulties, especially with expressive language, frustration-based outbursts, motor skills issue and developmental delays.  Also, there is a 20 times increased risk for XXY males to develop breast cancer than non XXY males.


For proper care and treatment early diagnosis is important. The treatment includes hormone therapy such as testosterone replacement. Other treatment aspects should include the psychosocial and emotional problems, needed treatment for physiological side affects and later on even genetic counseling.


Klinefelter Syndrome

Author: Harold Chen, MD, MS, FAAP, FACMG, Chief, Professor, Department of Pediatrics, Section of Perinatal Genetics, Louisiana State University Medical Center


Klinefelter Syndrome?

Or is he XXY? There IS a difference!

A Parent’s View


Understanding Klinefelter Syndrome

A Guide for XXY Males and Their Families

Written by:
Robert Bock
Office of Research Reporting, NICHD

NIH Pub. No. 93-3202
August 1993


What is Klinefelter Syndrome?
Chromosomes and Klinefelter Syndrome
What to Tell Families, Friends, and XXY boys
Detecting Language Problems Early
Guidelines for Detecting Language Problems
The XXY Boy in the Classroom
Help Under the Law
Teaching Tips
Testosterone Treatment
Chromosomal Variations
Health Considerations


Klinefelter’s Syndrome

Med Line Plus br /




Klinefelter Organization







Klinefelter Syndrome & Associates, Inc.
PO Box 119
Roseville, CA 95678-0119
Phone: 916.773.1449
Fax: 916.773.1449
Web site: (Japenese version)
[Note: group name may change to X & Y Family Genetic Network and include XXX, and XXY and the multiple sex chromosome variants]
Resources for families
Introductory video about XXY, by mother whose son has Klinefelter Syndrome
– The Even Exchange, Newsletter
American Association for Klinefelter Syndrome Information and Support (AAKSIS)

Klinefelter Syndrome Support Group Home Page, numerous links to other organizations and resources, created by an adult with Klinefelter Syndrome, regional groups, varients, international groups

International Groups:

Australian Klinefelter Support Group
4 Victoria Rd
Acquire Fields NEW 02564 AUSTRALIA
Victoria Support Group
41 Jesmond Rd
Cordon, Victoria 03136 AUSTRALIA

Klinefelter Syndrome Support Group
P.O.Box 3
Glendenning Mail Center NEW 2761 AUSTRALIA


Canada Klinefelter Support Group
Apt. 3, 2867 Young St.
Toronto, ON. Canada M4N 2J5
416. 481.3171

England (United Kingdom)

Klinefelter’s Syndrome Association
56 Little Yeldham Road
Little Yeldham, Halstead, Essex CO9 4QT
Klinefelter Organisation [formerly the Klinefelter’s Syndrome Club UK (KSCUK)]

Belgische vereniging voor het syndroom van Klinefelter

Sweden and Denmark

Swedish Klinefelter Association (Svenska XXY& Klinefelterföreningen)

Klinefelter Syndrome Booklets, Danish version or English version, The Turner Center

Norwegian Klinefelter Site

Other information:

Chromosomal Problems Discovered through Prenatal Diagnosis: Klinefelter Syndrome, (.pdf) PacNorGG spanish version

Diagnosis and Treatment of Klinefelter Syndrome, CM SMYTH, University of Washington, Hospital Practice, 1999

Guide for XXY Males and Their Families, R Bock, National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH)

Klinefelter Syndrome (47,XXY), English & Spanish (.pdf files), Pacific Northwest Regional Genetics Group (PacNoRGG)

Klinefelter Syndrome (XXY): A Parent’s View

Klinefelter Syndrome, eMedicine

Klinefelter Syndrome, Ohio Support Network

Misleading information in early Klinefelter studies

Human Growth Foundation

Teaching tips for males with XXY

The Turner Center Center for Information,Counseling, and Research on chromosome anomalies (includes Klinefelter Syndrome: An Orientation and Klinefelter Syndrome: Brief Information)

Understanding Klinefelter Syndrome: A Guide for XXY Males and their Families, R Boca, INCHED, NIHAU Pub. No. 93-3202, August 1993

XXY List Members

What is XXY? Hambley, (french version) XYY individual’s sites

What is chromosome 22?

Chromosome 22 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 22 is the second smallest human chromosome, spanning about 49 million base pairs (the building material of DNA) and representing between 1.5 and 2 percent of the total DNA in cells.

In 1999, researchers working on the Human Genome Project announced they had determined the sequence of base pairs that make up this chromosome. Chromosome 22 was the first human chromosome to be fully sequenced.

Identifying genes on each chromosome is an active area of genetic research. Because researchers use different approaches to predict the number of genes on each chromosome, the estimated number of genes varies. Chromosome 22 likely contains between 500 and 800 genes.

Genes on chromosome 22 are among the estimated 20,000 to 25,000 total genes in the human genome.

There are many conditions related to genes on chromosome 22.

What chromosomal conditions are related to chromosome 22?

The following conditions are caused by changes in the structure or number of copies of chromosome 22.

22q11.2 deletion syndrome
Most people with 22q11.2 deletion syndrome are missing about 3 million base pairs on one copy of chromosome 22 in each cell. The deletion occurs near the middle of the chromosome at a location designated as q11.2. This region contains about 30 genes, but many of these genes have not been well characterized. A small percentage of affected individuals have shorter deletions in the same region.

The loss of one particular gene, TBX1, is thought to be responsible for many of the characteristic features of 22q11.2 deletion syndrome, such as heart defects, an opening in the roof of the mouth (a cleft palate), distinctive facial features, and low calcium levels. A loss of this gene does not appear to cause learning disabilities, however. Other genes in the deleted region are also likely to contribute to the signs and symptoms of 22q11.2 deletion syndrome.

other chromosomal conditions
Other changes in the number or structure of chromosome 22 can have a variety of effects, including mental retardation, delayed development, physical abnormalities, and other medical problems. These changes include an extra piece of chromosome 22 in each cell (partial trisomy), a missing segment of the chromosome in each cell (partial monosomy), and a circular structure called ring chromosome 22 that is caused by the breakage and reattachment of both ends of the chromosome.

Cat-eye syndrome is a rare disorder most often caused by a chromosomal change called an inverted duplicated 22. A small extra chromosome is made up of genetic material from chromosome 22 that has been abnormally duplicated (copied). The extra genetic material causes the characteristic signs and symptoms of cat-eye syndrome, including an eye abnormality called ocular iris coloboma (a gap or split in the colored part of the eye), small skin tags or pits in front of the ear, heart defects, kidney problems, and, in some cases, delayed development.

A rearrangement (translocation) of genetic material between chromosomes 9 and 22 is associated with several types of blood cancer (leukemia). This chromosomal abnormality, which is commonly called the Philadelphia chromosome, is found only in cancer cells. The Philadelphia chromosome has been identified in most cases of a slowly progressing form of blood cancer called chronic myeloid leukemia, or CML. It also has been found in some cases of more rapidly progressing blood cancers (acute leukemias). The presence of the Philadelphia chromosome can help predict how the cancer will progress and provides a target for molecular therapies.

Is there a standard way to diagram chromosome 22?

Geneticists usediagrams called ideograms as a standard representation for chromosomes. Ideograms show a chromosome’s relative size and its banding pattern. A banding pattern is the characteristic pattern of dark and light bands that appears when a chromosome is stained with a chemical solution and then viewed under a microscope.These bands are used to describe the location of genes on each chromosome.

Ideogram of chromosome 22 See How do geneticists indicate the location of a gene? in the Handbook. Where can I find additional information about chromosome 22?

You may find the following resources about chromosome 22 helpful.

You may also be interested in these resources, which are designed for genetics professionals.

Where can I find general information about chromosomes?

The Handbook provides basic information about genetics in clear language.

These links provide additional genetics resources that may be useful.

What glossary definitions help with understanding chromosome 22?

acute ; base pair ; calcium ; cancer ; chromosome ; chronic ; cleft palate ; coloboma ; deletion ; DNA ; gene ; genome ; kidney ; learning disability ; leukemia ; mental retardation ; monosomy ; palate ; rearrangement ; ring chromosomes ; sign ; symptom ; translocation ; trisomy

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.

References (13 links) 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? in the Handbook.


Complete Trisomy 22


Chromosome 22 Central


237 Kent Avenue
Timmins, Ontario CANADA
P4N 3C2
(705) 268-3099


Chromosome 22 related Syndromes


Trisomy 22 Interest Board


Human Chromosome 22 Project Overview


National Organization for Rare Disorders, Inc.

Chromosome 22, Trisomy Mosaic

It is possible that the main title of the report Chromosome 22, Trisomy Mosaic is not the name you expected. Please check the
synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.


  • Trisomy 22 Mosaic
  • Trisomy 22 Mosaicism Syndrome

Disorder Subdivisions

  • None

General DiscussionChromosome 22, Trisomy Mosaic is a rare chromosomal disorder in which chromosome 22 appears three times (trisomy) rather than twice in some cells of the body. The term “mosaic” indicates that some cells contain the extra chromosome 22, whereas others have the normal chromosomal pair.

The range and severity of associated symptoms and findings may vary, depending upon the percentage of cells with the chromosomal abnormality. However, characteristic features typically include growth delays, mental retardation, unequal development of the two sides of the body (hemidystrophy), and webbing of the neck. Affected individuals may also have abnormal outward deviation of the elbows upon extension (cubitus valgus), multiple pigmented moles or birthmarks (nevi), distinctive malformations of the head and facial (craniofacial) area, and other physical abnormalities..


Resources Support Organization for Trisomy 18, 13, and Related Disorders
2982 South Union Street
Rochester, NY 14624-1926
Tel: (716)594-4621
Fax: (716)594-4621
Tel: (800)716-7638


March of Dimes Birth Defects Foundation
1275 Mamaroneck Avenue
White Plains, NY 10605
Tel: (914)428-7100
Fax: (914)997-4763
Tel: (888)663-4637
TDD: (914)997-4764


The Arc (a national organization on mental retardation)
1010 Wayne Ave
Suite 650
Silver Spring, MD 20910
Tel: (301)565-3842
Fax: (301)565-3843
Tel: (800)433-5255
TDD: (817)277-0553


National Organization for Rare Disorders, Inc.
55 Kenosia Ave
PO Box 1968
Danbury, CT 06813-1968
Tel: (203)744-0100
Fax: (203)798-2291
Tel: (800)999-6673
TDD: (203)797-9590


American Heart Association
National Center
7272 Greenville Avenue
Dallas, TX 75231-4596
Tel: (214)373-6300
Fax: (214)373-0268
Tel: (800)242-8721


Support Organization for Trisomy 13/18 and Related Disorders, UK
7 Orwell Road
Hampshire, Intl GU31 4LQ
United Kingdom
Tel: 0121-351-3122


UNIQUE – Rare Chromosome Disorder Support Group
P.O. Box 2189
Surrey, Intl CR3 5GN
United Kingdom
Tel: 4401883 330766
Fax: 4401883 330766


Congenital Heart Disease Resource Page
Web Site on the Internet



For a Complete Report

This isan abstract of a report from the National Organization for Rare Disorders, Inc. ® (NORD). A copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see

Trisomy 21

Alternative names   

Trisomy 21, Down Syndrome

Definition    Return to top

Down syndrome is a chromosome abnormality, usually due to an extra copy of the 21st chromosome. This syndrome usually, although not always, results in mental retardation and other conditions.

Causes, incidence, and risk factors    Return to top

In most cases, Down syndrome is caused by an extra chromosome 21. It is the most common single cause of human birth defects, with an occurence in 1 out of every 660 births.

Children with Down syndrome have a widely recognized characteristic appearance. The head may be smaller than normal (microcephaly) and abnormally shaped. Prominent facial features include a flattened nose, protruding tongue, and upward slanting eyes. The inner corner of the eyes may have a rounded fold of skin (epicanthal fold) rather than coming to a point. The hands are short and broad with short fingers and often have a single crease in the palm (simian crease). Retardation of normal growth and development is typical and most affected children never reach average adult height.

Congenital heart defects are frequently present in Down syndrome children. Early mortality is often a result of cardiac abnormalities. Gastrointestinal abnormalities such as esophageal atresia (obstruction of the esophagus) and duodenal atresia (obstruction of the duodenum) are also relatively common. Obstruction of the gastrointestinal tract may require major surgery shortly after birth. Children with Down syndrome also have a higher than average incidence of acute lymphocytic leukemia (ALL).

Symptoms    Return to top

  • Decreased muscle tone at birth
  • Separated sutures (joints between the bones of the skull)
  • Asymmetrical or odd-shaped skull
    • Round head with flat area at the back of the head (occiput)
    • Small skull (microcephaly)
  • Upward slanting eyes, unusual for ethnic group
  • Small mouth with protruding tongue (see tongue problems)
  • Broad short hands
  • Single crease on the palm
  • Retarded growth and development
  • Delayed mental and social skills (mental retardation)
  • Iris lesion (an abnormality of the colored part of the eye called Brushfield spots)

Signs and tests    Return to top

A heart murmur may be revealed by listening to the chest with a stethoscope. Characteristic abnormalities are revealed by a physical examination. These include a flattened facial profile, small ears, separation of the abdominal muscles, joint hyperflexibility, awkward gait, extra skin on back of neck at birth, and an abnormal bone in the middle of the 5th finger.

Early and massive vomiting may indicate obstruction of the esophagus or duodenum and less often lower segments of the gastrointestinal tract. This is sometimes discovered by inability at birth to pass a tube from the nose into the stomach or duodenum as well as by special x-rays.

Tests include:

  • Chromosome studies (demonstrates three copies of 21st chromosome in 94% of cases)
  • Chest x-ray (to determine presence of cardiac abnormalities)
  • Echocardiogram (to determine nature of cardiac abnormality)
  • ECG
  • Gastrointestinal x-ray (to show obstruction if symptoms are suggestive)

Treatment    Return to top

There is no specific treatment for Down syndrome. Special education and training is offered in most communities for mentally handicapped children. Specific heart defects may require surgical correction. The potential for visual problems, hearing loss, and increased susceptibility to infection will require screening and treatment at appropriate intervals.

Support Groups    Return to top

National Down Syndrome Congress
1370 Center Drive, Suite 102
Atlanta, GA 30338

Expectations (prognosis)    Return to top

The normal life span is shortened in Down syndrome by congenital heart disease and by increased incidence of acute leukemia. Mental retardation is variable although usually of moderate severity. Some adults live independently and are accomplished individuals.

Complications    Return to top

  • Vision problems
  • Hearing loss
  • Cardiac abnormalities
  • Increased incidence of acute leukemia
  • Frequent ear infections and increased susceptibility to infection in general
  • Gastrointestinal obstruction (imperforate anus, and similar problems)
  • Esophageal atresia or duodenal atresia
  • Blocked airways during sleep (one third of patients)
  • Increased incidence of dementia in older patients
  • Instability of the back bones at the top of the neck, compression injury of the spinal cord

There is a risk that uninformed people may assume a Down syndrome child is more retarded than he or she is.

Calling your health care provider    Return to top

A geneticist should be consulted to help determine the diagnosis and interpret rare chromosomal translocation cases of Down syndrome.

The health care provider should be consulted to evaluate the child for the need for special education and training. The need for follow-up of physical problems varies.

Prevention    Return to top

Genetic counseling is recommended in all families with Down syndrome. Down syndrome can be detected in a fetus in the first few months of pregnancy by examination of the chromosomes obtained by amniocentesis or chorionic villus sampling. The parents of a child with Down syndrome are at increased risk for having another child with Down syndrome. Mothers who become pregnant after age 40 are also at increased risk for having a child with Down syndrome.

Update Date: 8/19/2003

Updated by: Douglas R. Stewart, M.D., Division of Medical Genetics, Hospital of the University of Pennsylvania, Philadelphia, PA. Review provided by VeriMed Healthcare Network.


Directory of Down Syndrome Sites

…………National Down Syndrome Society


Down Syndrome: Health Issues…………

Trisomy 21: The Story of Down Syndrome




Trisomy 21 Online Community

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