Clinical Diagnosis

Chromosome 2q37 deletion syndrome is suspected in individuals with the following characteristics:

• Developmental delay/intellectual disability

• Brachymetaphalangy of digits 3-5 (often digit 4 alone)

• Short stature

• Obesity

• Hypotonia

• Characteristic facial appearance:

  • Round face (variable)

  • Frontal bossing

  • Arched eyebrows

  • Deep-set eyes

  • Upslanted palpebral fissures

  • Epicanthal folds

  • Hypoplastic alae nasi

  • Prominent columella

  • Thin upper lip

  • Minor ear anomalies

• Autism or autistic-spectrum disorder

• Joint hypermobility/dislocation, scoliosis

Note: When present together, the first four features (developmental delay/intellectual disability, brachymetaphalangy of digits 3-5, short stature, obesity) are often referred to as the "Albright hereditary osteodystrophy (AHO)-like phenotype."

Other structural anomalies

• Congenital heart disease (atrial/ventricular septal defects, PDA)

• CNS abnormalities (hydrocephalus, dilated ventricles)

• Umbilical/inguinal hernia

• Tracheomalacia

• Situs abnormalities

• Gastrointestinal abnormalities

• Renal malformations

Other clinical findings

• Seizures

• Eczema

• Osteopenia

• Behavioral problems (hyperactivity, attention deficits)

Neoplasms. Wilms tumor

Testing

Cytogenetic testing. Chromosome analysis typically confirms the diagnosis of 2q37 deletion syndrome.

In about 15%-20% of cases, the conventional karyotype is normal because of the small size of the deleted region [Shrimpton et al 2004, Aldred 2006, Lacbawan et al 2006]. Cryptic 2q37 deletions (deletions that are not visible with routine cytogenetics) have been reported in persons with the AHO-like phenotype [Bijlsma et al 1999, Giardino et al 2002, Chassaing et al 2004]. Small terminal deletions of 2q may be missed on routine cytogenetic studies, and minute deletions may be undetectable unless more detailed analysis using FISH, microsatellite markers, CGH, or other molecular techniques are employed.

Some individuals with the 2q37 deletion syndrome have chromosomal rearrangements involving 2q37, such as ring chromosome 2 or translocation between chromosome 2 and another chromosome that results in deletion of 2q37.

Molecular Genetic Testing

Genes. The largest reported telomeric deletion in the 2q37 chromosomal region is about 10 Mb while the smallest is less than 4 Mb [Aldred 2006, Lacbawan et al 2006]. Deletion of the genes in this chromosome region is the only genetic defect known to be associated with deletion 2q37.

Proposed candidate genes responsible for the AHO-like phenotype in individuals with 2q37 deletion syndrome include the following:

• Classic Albright hereditary osteodystrophy is caused by a deletion or mutation in the alpha subunit of a G-protein gene (GNAS) (see Differential Diagnosis). Shrimpton et al [2004] proposed candidate GPR35 because it codes for a G-protein-coupled receptor. The authors hypothesized that GPR35 acts as a receptor of the GNAS protein. Haploinsufficiency of GPR35 would therefore affect the same molecular pathway, and result in a similar clinical phenotype. Similarly, Davids et al [2001] proposed candidate STK25 because it codes for a serine-threonine kinase known to interact with the beta subunit of G proteins. Smith et al [2001] and Syrrou et al [2002] proposed candidate GPC1, which encodes glypican 1, because it could cause skeletal anomalies. Deletions or mutations of a similar gene, GPC3, have been found in Simpson-Golabi-Behmel syndrome [Pilia et al 1996], a syndrome that includes skeletal anomalies.

• Power et al [1997] postulated that hemizygosity of RDCI, a vasoactive intestinal peptide receptor, leads to the AHO-like phenotype in persons with 2q37 deletions.

Proposed candidate genes responsible for the autistic features in individuals with 2q37 deletion syndrome include the following:

• Smith et al [2001] suggested that potential gene candidates for autism must be abundantly expressed in the brain and influence brain development. Besides GPC1, KIF1A (also known as ATSV, axonal transporter of synaptic vesicle), HDLBP (encoding vigilin, a high-density lipoprotein-binding protein; involved in RNA binding and transport from nucleus to cytoplasm), and GBX2 were mentioned. (See Autism Overview.)

• Lukusa et al [2004] considered CENTG2 a candidate gene, in addition to GBX2, which encodes gastrulation homeobox 2.

• Wassink et al [2005] also proposed CENTG2 because it is a cytoskeleton protein involved in multiple neuronal processes. They conducted a linkage study of 117 families with at least two siblings affected by autism, and screened 199 independent autistic individuals. Their results were mixed in terms of supporting the causative role of CENTG2 in autism.

Clinical testing

• FISH. Subtelomeric 2q probes are commercially available (Cytocell; Vysis). A subtelomeric FISH probe should confirm the vast majority of chromosome 2q37 deletions. Theoretically, an interstitial 2q37 deletion could be missed if the subtelomeric sequence is present [Aldred et al 2004, Chaabouni et al 2006].

• Array comparative genomic hybridization (CGH) (using BAC clones). This test was used to confirm a cryptic unbalanced translocation involving 2q37.2 in a spontaneously aborted fetus after cultured embryonic tissue failed to grow [Bruyere et al 2003]. Most 2q37 deletions are detectable with commercially available array CGH, although more precise mapping of the deleted region is typically performed only on a research basis [Aldred et al 2004; Shrimpton et al 2004; Lacbawan et al, unpublished].

Although submicroscopic deletions are demonstrated using FISH or array CGH, concurrent duplication/deletion may be missed by FISH study [Lacbawan et al 2006].

Research testing. Refinement of the molecular breakpoints in individuals with pure 2q37 deletion and clinical correlation studies are ongoing [Lacbawan et al 2006].

Table 1. Summary of Molecular Genetic Testing Used in 2q37 Deletion Syndrome

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Test Method	Mutations Detected	Mutation Detection Frequency by Test Method	Test Availability
Routine karyotype	Deletion of chromosome 2q37	80%-85%	Clinical
FISH of subtelomeric 2q region		>99%	Clinical
Array comparative genomic hybridization			Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

Testing Strategy

To establish the diagnosis of 2q37 deletion in a proband, the following testing should be performed:

• Karyotype (i.e., routine cytogenetic study)

• If the chromosome study is normal but the index of suspicion is high, subtelomere FISH study or array CGH

• If FISH study is normal, array comparative genomic hybridization (using BAC clones)

• If clinically available in the future, consideration of oligonucleotide array CGH to define the extent of the deletion and/or rule out associated duplication and, eventually, facilitate anticipatory management for the affected individual

Prenatal diagnosis for at-risk pregnancies requires prior confirmation of the diagnosis of 2q37 deletion syndrome in the proband and/or of balanced carrier status in a parent.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

The 2q37 deletion syndrome may present with a broad spectrum of clinical findings, however, no other phenotypes are known to be associated with deletion of 2q37. A thorough review of cases reported with a subtelomeric 2q deletion is pending. However, we note that isolated subtelomeric 2q37 deletions were found in several large studies of individuals with normal chromosomes and developmental delay/intellectual disability with or without other dysmorphic features [Anderlid et al 2002, Sogaard et al 2005, Ravnan et al 2006]. The 2q37 deletion syndrome phenotype was not clearly described in any of these individuals. A pilot study of children with autism reported one nondysmorphic child with a normal examination and a subtelomeric deletion of 2q [Wolff et al 2002]. Further molecular characterization of these individuals would be helpful.

Natural History

The 2q37 deletion syndrome may present with a broad spectrum of clinical findings as described below [Smith et al 2001, Casas et al 2004, Chassaing et al 2004, Lacbawan et al 2005, Aldred 2006, Chaabouni et al 2006, Kitsiou-Tzeli et al 2007, Lacbawan et al 2006].

In individuals with isolated deletion 2q37 (i.e., those without an unbalanced translocation), functional outcome was affected by the presence of autism, developmental delay, and/or major congenital anomalies.

The phenotype observed in individuals with 2q37 deletion syndrome seems variable in earlier reports because the molecular breakpoints were not defined.

The female-to-male ratio is greater than one.

Developmental delay. Most affected individuals have mild-moderate developmental delay. However, one individual with delayed developmental milestones was reported to work as a librarian's assistant and a second individual was a college student with autism and average-range cognitive function.

Autism or autistic spectrum disorder. 2q37 deletions are common in individuals with syndromic autism [Jacquemont et al 2006]. Approximately one-third of those reported with 2q37 deletion syndrome have autism or autistic features, which show significant variation among individuals. Nonetheless, no behavioral phenotype appears to be specific to the 2q37 deletion syndrome.

Brachymetaphalangy. Short metacarpals/metatarsals of digits 3-5, often digit 4 alone, is present in more than half of reported cases. No functional implications are associated with the shortened digit(s). Brachymetaphalangy may not be clinically apparent in young children, though this feature has been described in several children under age one year.

Growth. The incidence of short stature is increased in individuals with 2q37 deletion syndrome. Failure to thrive is sometimes reported in affected infants.

Obesity. Obesity may be noted in childhood. The prevalence of obesity appears to increase with age.

Hypotonia. A significant number of individuals with 2q37 deletion have hypotonia and feeding difficulties. Genu valgum/recurvatum and pes planus are also common.

Characteristic facial appearance and other dysmorphic features. The typical facial characteristics include thin, arched eyebrows with deeply set eyes, hypoplastic nares, prominent columella, thin vermilion border, and minor ear dysmorphism with or without round face. The facial phenotype can be subtle, and may not be easily recognized by less experienced clinicians. Use of stereophotogrammetry has been shown to be able to distinguish the facial phenotype.

Low-set, hypoplastic nipples are often seen. Joint hyperextensibility and skin hyperlaxity may be observed.

Seizures. Approximately 20%-35% of reported cases have had some type of seizures. Grand mal, partial, and myoclonic seizures have all been reported, however, very little clinical information is provided in most reports.

Eczema. Moderate-to-severe eczema has been reported in a few individuals.

Osteopenia. Though osteopenia is not well known to be associated with 2q37 deletion, a number of affected individuals have had osteopenia on further radiologic studies. Clinical implications have not been described.

Gastroesophageal reflux (GER). Moderate-to-severe GER can occur, and can be severe enough to necessitate surgical intervention.

Wilms tumor. Two individuals with 2q37 deletion syndrome and Wilms tumor have been reported [Conrad et al 1995, Viot-Szoboszlai et al 1998]. Both children presented before age two years.

Other structural anomalies [Reddy et al 1999, Lehman et al 2001, Aldred 2006, Masumoto et al 2006]:

• Cleft palate

• Congenital hearing loss

• Congenital heart disease (typically atrial/ventricular septal defects)

• Situs abnormalities

• Renal malformations including horseshoe kidney

• CNS abnormalities including separate cases reported with holoprosencephaly, agenesis of the corpus callosum, and hydrocephalus

• Gastrointestinal abnormalities, including hiatal hernia, pyloric stenosis, malrotation, anal atresia, and esophageal atresia

• Joint hypermobility/dislocation and scoliosis

• Umbilical/inguinal hernia

Life span. The presence of congenital malformations appears to be the single greatest factor in determining life expectancy. Few older adults have been reported with 2q37 deletion syndrome; however, the authors anticipate that this will change as more individuals are ascertained with the use of subtelomeric FISH and array CGH studies and longitudinal data are collected on those with the disorder.

Genotype-Phenotype Correlations

Penetrance is complete in the 2q37 deletion syndrome; however, phenotypic variability is observed. Using both cytogenetic and molecular analysis, deletion size does not appear to correlate well with phenotype. Minimal deletion intervals for critical features of the 2q37 deletion syndrome were proposed by Aldred [2006] and have been refined in several subsequent publications.

Parent-of-origin effect has not been convincingly demonstrated.

Penetrance

Clinical characteristics of 2q37 deletion syndrome are apparent and no case of mosaicism has been documented to date.

Nomenclature

The 2q37 deletion syndrome has also been referred to as Albright hereditary osteodystrophy 3.

Prevalence

The prevalence of the 2q37 deletion syndrome is unknown. It is likely that this syndrome is underdiagnosed because of difficulty recognizing a small terminal deletion on routine cytogenetic studies, and failure to recognize a clinical syndrome on physical examination. It is expected that more individuals will be diagnosed as the clinical use of subtelomeric FISH and comparative genomic hybridization studies increases.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with the 2q37 deletion 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, autistic-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 deletion 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.

Treatment of Manifestations

Depending on the age and presenting concerns of the individual with the 2q37 deletion syndrome, care from specialists in the following areas is often necessary: medical genetics, speech pathology, occupational and physical therapy, child development, neurology, cardiology, gastroenterology, dietician or other obesity specialist or feeding team in cases of failure to thrive, ophthalmology, and audiology.

Medical care may be coordinated by a medical 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 multi-specialty group of physical, occupational, and speech therapists with pediatric assessment.

Prevention of Secondary Complications

At this time, it is not known why many individuals with the 2q37 deletion syndrome are obese. To the extent that it is feasible, the authors recommend an active lifestyle and good dietary habits to help avoid development of obesity.

Surveillance

The following are appropriate:

• Ongoing routine pediatric care

• Periodic reevaluation by a medical 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.

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

2q37 deletion syndrome can be the result of a de novo chromosome abnormality or may be inherited from a parent who is a balanced translocation carrier.

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 approximately 5% of published cases [Bijlsma et al 1999, Speleman et al 2000, Wiktor et al 2001, Giardino et al 2002, Bruyere et al 2003]; there are approximately 100 published cases without a familial translocation.

• Parents of a proband with a structurally unbalanced chromosome constitution (e.g., deletion or translocation) are at risk of having a balanced chromosome rearrangement and should be offered chromosome analysis.

Sibs of a proband

• The risk to sibs of a proband with 2q37 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.

• The occurrence of germline mosaicism has not been reported in individuals with 2q37 deletion syndrome, although the possibility cannot be excluded.

Offspring of a proband. While there are no published reports of individuals with 2q37 deletion syndrome reproducing to date, menarche was reported in an adolescent girl who subsequently experienced secondary amenorrhea [Wilson et al 1995], and the authors have personally examined a second female with normal menses. It is reasonable to expect normal fertility in mildly affected individuals with the 2q37 deletion syndrome. In this case, the risk of transmitting the chromosome deletion would be 50% for each pregnancy.

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 has 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 of fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. It is difficult to visualize terminal chromosome deletions in fetal cells; therefore, confirmation of the result with FISH should be performed.

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

Preimplantation genetic diagnosis (PGD) may be available for families at increased risk for a pregnancy with 2q37 syndrome. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

To date, fine molecular mapping of the 2q37 deletion in affected individuals has not uncovered a common breakpoint, and the severity of the syndrome does not seem to correlate well with the size of the deletion.

The critical region for brachydactyly has been mapped to HDAC proximally and STK25 distally in the terminal 3 Mb of chromosome 2q [Chaabouni et al 2006].

A candidate gene for autism in the 2q37 deletion syndrome, CENTG2, is located approximately 6 Mb from the 2q terminus [Wassink et al 2005].

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Acknowledgments

We are indebted to the affected individuals we work with and their families. This work was supported by the Division of Intramural Research, National Human Genome Research Institute, and National Institutes of Health.

Revision History

• 3 May 2007 (me) Review posted live

• 21 March 2007 (esd) Original submission