Clinical Diagnosis

The clinical spectrum of the 9q22.3 microdeletion is variable and the clinical findings depend somewhat on the size of the microdeletion.

All reported 9q22.3 microdeletions include PTCH1, the gene that is mutated in Gorlin syndrome (nevoid basal cell carcinoma syndrome); therefore, all individuals with 9q22.3 microdeletion have the clinical findings of this well-described disorder [Kimonis et al 2004].

Major features of Gorlin syndrome include:

• Lamellar calcification of the falx cerebri prior to age 20 years

• Five or more basal cell carcinomas in a lifetime or one prior to age 30 years

• Jaw keratocysts

• Palmar/plantar pits

• First-degree relative with Gorlin syndrome

Minor features of Gorlin syndrome include [Kimonis et al 2004]:

• Cleft lip and/or cleft palate

• Pre- or postaxial polydactyly

• Macrocephaly (occipital-frontal circumference of >97th percentile)

• Ocular anomalies (including microphthalmia, cataracts, retinal anomalies, developmental defects)

• Rib and/or vertebral anomalies

• Cardiac and ovarian fibromas

• Childhood medulloblastoma (also called primitive neuroectodermal tumor [PNET])

• Lymphomesenteric or pleural cysts

Additional findings common in 9q22.3 microdeletion include [Muller et al 2011]:

• Developmental delay and/or intellectual disability

• Short nose and long and tented philtrum

• Metopic craniosynostosis

• Obstructive hydrocephalus

• Pre- and postnatal height and weight of >95th percentile

• Seizures

Occasional abnormalities in 9q22.3 microdeletion may include renal anomalies, Chiari malformation, and dysgenesis of the corpus callosum.

Testing

Cytogenetic testing. The 9q22.3 microdeletion cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques, except with extremely large deletions.

Molecular Genetic Testing

Critical region. The diagnosis of the 9q22.3 microdeletion is confirmed by demonstration of a heterozygous microdeletion at chromosome 9q22.3. The minimal critical region that is deleted recurrently in affected individuals, but not in controls, is 352 kb, and includes the genes PTCH1 (human homolog 1 of Drosophila Patched) and FANCC (Fanconi anemia complementation group C) [Muller et al 2011].

Gene. PTCH1 is the only gene of which deletion is known to account for the majority of features in 9q22.3 microdeletion; however, deletion of this gene does not appear to be sufficient to cause the features that are distinct from those usually seen in Gorlin syndrome. Among the two to 273 genes included within the interval of this contiguous gene deletion are genes that encode microRNAs, transcription factors, uncharacterized open reading frames, and proteins of unknown function [Muller et al 2011]. Many of these genes remain uncharacterized as to their individual deletion or mutation phenotypes.

Note: The genes that are deleted vary with the size and breakpoints of the microdeletion.

Clinical testing

Deletion/duplication analysis. The 9q22.3 microdeletion can be detected by any molecular method that determines the copy number of genomic sequences within the deleted region. Either whole-genome or targeted approaches can be used:

• Chromosomal microarray (CMA) using arrays of BACs, oligonucleotides, or SNPs can detect the 352-kb minimal critical deletion along with larger deletions. The ability to determine that the deletion involves the 352-kb critical region depends on both the type of microarray used and the density of probes in the 9q22.3 region. Note: Depending on the resolution, some chromosomal microarrays used before 2008 may not have been effective in detecting this deletion.

• Targeted deletion analysis. Targeted methods that can be used if the deletion is suspected clinically include fluorescence in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA).
  
  Note: (1) Whether or not the size of the deletion can be determined depends on the number and distribution of probes in the 9q22.3 region. (2) The size of a deletion cannot be determined by a single FISH or MLPA probe.

Table 1. Summary of Molecular Genetic Testing Used in 9q22.3 Microdeletion

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Chromosomal Region	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
9q22.3	Chromosomal microarray (CMA)	Deletion of 352 kb to 20.5 Mb in size	>99% with appropriate BACs, SNPs, or oligonucleotides	Clinical
	Deletion/ duplication analysis 2		>99% with appropriate probes	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.

1. The ability of the test method used to detect the indicated deletion

2. Testing that identifies deletions/duplications; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used.

Interpretation of test results

• Deletion analysis. Depending on the initial test that identifies the deletion, confirmation of the deletion by an independent method may be warranted. If high-density genomic microarray platforms have been used for the identification of the deletion, confirmation of the deletion may not be necessary, as it is unlikely that many adjacent targets would show an abnormal copy number by chance.

Testing Strategy

To confirm/establish the diagnosis in a proband requires detection of the 352-kb minimal critical deletion common in 9q22.3 microdeletion or any larger overlapping deletion.

• If the 9q22.3 microdeletion is suspected based on the clinical features, a targeted technique (e.g., FISH, MLPA) can be employed.

• Deletions may also be detected by genomic chromosomal microarray (CMA) analysis performed as part of the evaluation of developmental delay or intellectual disability, and/or after detection of a whole PTCH1 deletion.

Note: The deletion cannot be identified by routine chromosome analysis.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the deletion 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

Duplication of the 9q22.3 region, consisting of a 360-kb region containing PTCH1 and exon 1 of FANCC, has been described in a mother and her child. Both had microcephaly and mild developmental delay [Derwinska et al 2009].

Germline dominant loss of function mutations in PTCH1 including intragenic or whole-gene deletions are known to result in Gorlin syndrome [Hahn et al 1996].

Somatic dominant loss of function mutations in PTCH1 have been described in sporadic cancers that are also present in Gorlin syndrome, including medulloblastomas, odontogenic keratocysts, cardiac and ovarian fibromas, and basal cell carcinomas [Kimonis et al 2004].

Germline dominant gain of function mutations in PTCH1 associated with holoprosencephaly type 7 [OMIM 610828] that are consistent with reduced embryologic sonic hedgehog expression have been described in a few individuals [Ming et al 2002, Ribeiro et al 2006].

Natural History

Many individuals with 9q22.3 microdeletion exhibit hypotonia in infancy and all exhibit gross motor delay. Hypotonia may persist even into late childhood and adolescence in individuals with larger deletions [Shimojima et al 2009; Yamamoto et al 2009; Muller et al 2011]. Individuals with the smallest deletions may have resolution of their motor delay and have no other impairments or delays.

Individuals with deletions of approximately 2 Mb or larger exhibit persistent delays in attaining motor, speech, and behavioral/social milestones [Shimojima et al 2009; Muller et al 2011]. Individuals with these larger-sized deletions typically have intellectual impairment that becomes apparent at school age, requiring special education. More severe or profound disability is expected with increasing deletion size; IQ or developmental quotient (DQ) scores in the 30s to 40s or lower have been reported [Kroes et al 1994; Redon et al 2006; Fujii et al 2007; Nowakowska et al 2007; Yamamoto et al 2009; Muller et al 2011].

A fraction of all individuals with 9q22.3 microdeletion develop seizures [Shimojima et al 2009; Yamamoto et al 2009; Muller et al 2011].

Sixteen of 37 individuals reported with 9q22.3 microdeletion have cerebral ventricular dilation that ranges from severe to mild and asymmetric, and can be associated with cerebral atrophy or a space-occupying lesion (e.g., medulloblastoma) [Muller et al 2011]. Of those 16, seven have severe obstructive hydrocephalus of unknown etiology that requires ventricular shunting [Muller et al 2011].

Approximately 20% of individuals with 9q22.3 microdeletion have prenatal onset of macrosomia characterized by birth length and weight above the 95^th percentile, which continues postnatally [Muller et al 2011].

A few case reports describe either macrosomia or hemihyperplasia in individuals with 9q22.3 microdeletion [Cajaiba et al 2006; Chen et al 2006; Redon et al 2006; Shimojima et al 2009; Yamamoto et al 2009; Muller et al 2011].

Eight of 37 affected individuals reported by Muller et al [2011] exhibited early fusion of the metopic suture, resulting in metopic craniosynostosis and trigonocephaly.

Cajaiba et al [2006] described a single individual with Wilms tumor and a pelvic rhabdomyosarcoma and concluded that although Wilms tumor is not associated with Gorlin syndrome, rhabdomyosarcoma can be [Cajaiba et al 2006]. Currently, no evidence suggests that individuals with 9q22.3 microdeletion are at increased risk for intra-abdominal embryonal tumors such as those seen in Beckwith-Wiedemann syndrome; however, given the loss of the tumor suppressor gene PTCH1, which is located within the critical region, the risk of developing one of the tumor types associated with Gorlin syndrome is increased [Hahn et al 1996].

Affected individuals may have a facial gestalt that includes a broad forehead with bossing, vertical forehead creases, angulated palpebral fissures that may be either up- or downslanting, and a short nose with a long and tented philtrum [Ying et al 1982; Farrell et al 1991; Olivieri et al 2003; Midro et al 2004; Redon et al 2006; Nowakowska et al 2007; Yamamoto et al 2009; Muller et al 2011]. The facial features in some individuals tend to coarsen over time, whereas those with extremely large deletions may have coarse features at birth [Ying et al 1982; Muller et al 2011].

Genotype-Phenotype Correlations

Many of the features seen in individuals with 9q22.3 microdeletion result from haploinsufficiency of PTCH1, and as such are consistent with Gorlin syndrome. However, as all reported individuals to date have had many more genes than PTCH1 within their deletion, it is expected that deletion of one or more of these other genes results in the additional phenotypic features that are not characteristic of Gorlin syndrome.

Muller et al [2011] identified the minimal common deletion intervals and the associated breakpoints in ten individuals with 9q22.3 microdeletion for the following findings:

• Metopic craniosynostosis: a 929-kb region containing 16 genes

• Severe obstructive hydrocephalus: a 1.08-Mb region containing 18 genes

• Macrosomia: a 1.8-Mb region containing 31 genes

Note: Numerous genes within these intervals have not been fully characterized, and no specific candidate genes were identified.

Multiple authors have proposed that the macrosomia present in a subset of individuals with 9q22.3 microdeletion is specifically the result of loss of the paternal allele [Redon et al 2006, Shimojima et al 2009]. However, thus far, no imprinted genes within the deletion intervals have been identified.

Penetrance

It is expected that 9q22.3 microdeletion is fully penetrant for phenotype, but with variable expressivity. No unaffected individuals with this microdeletion have been reported to date.

Prevalence

The 9q22.3 microdeletion is presumably rare. To date, 37 affected individuals have been reported in the medical literature [Yamamoto et al 2009; Muller et al 2011]. It is likely that 9q22.3 microdeletion represents a very small fraction of individuals with dysmorphic features and developmental delay and/or intellectual impairment in the absence of other characteristic features.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with the 9q22.3 microdeletion, the following evaluations are recommended:

• Brain imaging (not using CT) and neurologic evaluation

• Complete physical examination, including dermatologic assessment for the manifestations of Gorlin syndrome

• Comprehensive developmental assessment

• Renal and pelvic ultrasound examination for evaluation of possible renal anomalies and ovarian fibromas

• Echocardiogram

• Ophthalmologic evaluation

• Careful consideration of skeletal and/or dental imaging for associated anomalies

• Familial genetic counseling

• Routine treatment and management by appropriate specialists for cardiac, neurologic, dermatologic findings

• Comprehensive physical, occupational, and speech therapy services as needed

• Surgical intervention as needed for excision or treatment of mandibular keratocysts, basal cell carcinomas, or other tumors that develop, or for management or correction of physical anomalies.

Treatment of Manifestations

The following are appropriate:

• Routine treatment and management by appropriate specialists for cardiac, neurologic, dermatologic findings

• Comprehensive physical, occupational, and speech therapy services as needed

• Surgical intervention as needed for excision or treatment of mandibular keratocysts, basal cell carcinomas, or other tumors that develop, or for management or correction of physical anomalies.

Prevention of Primary Manifestations

Avoidance of excessive sunlight or other ultraviolet radiation, and limiting exposure to ionizing radiation (e.g., by computed tomography and x-ray) is recommended because of the increased predisposition for the development of basal cell carcinomas.

Surveillance

The following recommended surveillance is the same as that for Gorlin syndrome (see Gorlin Syndrome).

• Head circumference should be followed throughout childhood and plotted on appropriate growth charts. Rapid enlargement should prompt evaluation for possible hydrocephalus.

• Awareness of the risk of medulloblastoma in the first years of life is important and may justify developmental assessment and physical examination every six months. No evidence for the efficacy of regular neuroimaging exists; frequent computer tomography (CT) should be avoided because of risks associated with radiation sensitivity.

• Orthopantogram is indicated every 12-18 months in individuals older than age eight years to identify jaw keratocysts.

• Skin should be examined at least annually; some physicians recommend skin examination by a professional every three to four months.

No evidence currently supports routine monitoring for intra-abdominal embryonal tumors by ultrasonography and/or serum AFP measurements for individuals with 9q22.3 microdeletion who have macrosomia or hemihyperplasia.

Agents/Circumstances to Avoid

As all individuals to date have had involvement of PTCH1 resulting in Gorlin syndrome, affected individuals are at increased risk for malignant tumor formation with ionizing and ultraviolet radiation exposure, and for spontaneous development of basal cell carcinomas both from the numerous existing basal cell nevi and in apparently unaffected skin (see Gorlin Syndrome). Radiographs and computed tomography should be used sparingly, and the benefit versus risk to the individual’s health should be carefully considered.

Liberal use of topical sunblock and avoidance of excessive exposure to sunlight are warranted.

Evaluation 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.

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

The 9q22.3 microdeletion is inherited in an autosomal dominant manner. All cases have resulted from either an apparent de novo event or inheritance of an unbalanced chromosome rearrangement from a parent with a balanced rearrangement.

Risk to Family Members

Parents of a proband

• Somatic/germline mosaicism has not been reported in an asymptomatic parent of an affected individual.

• Recurrence in two families in which a parent had a balanced translocation involving the 9q22.3 region has been reported [Shimkets et al 1996, Midro et al 2004].

• Recommendations for the evaluation of parents of a proband include cytogenetic evaluation to determine if a balanced chromosomal rearrangement involving 9q22.3 is present.

Sibs of a proband

• The risk to the sibs of the proband depends on the status of the parents.

• Recurrence risk to the sibs of a proband is low (probably <5%) but greater than that of the general population because a parent may have (i) germline mosaicism, or (ii) low-level somatic mosaicism that also includes the germline.

• If a parent has a balanced structural chromosome rearrangement involving the 9q22.3 critical region, the risk to sibs is increased and depends on the specific chromosome rearrangement.

Offspring of a proband. No individuals diagnosed with the typical 9q22.3 microdeletion have been known to reproduce.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent has a balanced chromosome rearrangement, his/her family members may be at increased risk of also having the rearrangement.

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. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 9q22.3 microdeletion.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal testing is technically feasible. Chromosome preparations from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or CVS at approximately ten to 12 weeks' gestation can be analyzed using a cytogenetics evaluation method in the same manner described in Molecular Genetic Testing.

Prenatal testing may be offered to parents who have had a child with the 9q22.3 microdeletion because of the recurrence risk (probably <5%) associated with the possibility of germline mosaicism. Prenatal testing is also offered to parents who carry a balanced chromosome rearrangement.

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 in which the 9q22.3 deletion has been identified. 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

The mechanism that predisposes the 9q22.3 region to deletion is unclear. The numerous SINEs, large LINEs, and LTRs that flank PTCH1 and adjacent genes in the region potentially could predispose to recombination events that result in deletion or duplication of these genes. Similarly, it is unknown how deletion of genes, other than PTCH1, within the 9q22.3 microdeletion results in the phenotype, as the function and haploinsufficiency phenotype of many of the 273 genes in the largest reported deletion of 20.5 Mb remain uncharacterized [Muller et al 2011].

The microdeletion size among the reported affected individuals does not appear to be recurrent. The earliest reports of 9q22.3 deletions preceded CMA technology; at that time only large deletions visible by routine cytogenetic banding techniques were described, making specific breakpoint comparison with reports from the last several years difficult. Following the availability of CMA technology, the minimal interstitial 9q22.3 microdeletion reported contains only two genes, PTCH1 and FANCC [Muller et al 2011].

PTCH1 (human homolog 1 of Drosophila Patched) encodes a tumor suppressor protein that is the receptor for sonic hedgehog (SHH) protein, which in the unbound form normally acts to repress SHH signaling. FANCC (Fanconi anemia complementation group C) encodes a protein that is part of the core FA nuclear protein complex with E3 ubiquitin ligase activity which activates in response to DNA damage and in the S-phase. Homozygous or compound heterozygous mutations in this gene result in Fanconi anemia.

In ten individuals with 9q22.3 microdeletion, Muller et al [2011] attempted to define the critical regions and genes involved in the three distinctive features metopic craniosynostosis, obstructive hydrocephalus, and macrosomia; using this approach they were able to narrow the overlapping regions to 0.929 to 1.8 Mb. The shared genes within these intervals are summarized in Figure 1.

Figure

Figure 1. Schematic of genes involved in ten individuals with 9q22.3 microdeletion and shared phenotypes

Literature Cited

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Revision History

• 18 August 2011 (me) Review posted live

• 25 April 2011 (em) Original submission