Clinical Diagnosis

The otopalatodigital (OPD) spectrum disorders, a heterogeneous group of disorders characterized primarily by a skeletal dysplasia of variable severity, include the following [Verloes et al 2000]:

• Otopalatodigital syndrome type I (OPD1)
• Otopalatodigital syndrome type II (OPD2)
• Frontometaphyseal dysplasia (FMD)
• Melnick-Needles syndrome (MNS)
• Terminal osseous dysplasia with pigmentary skin defects (TODPD) [Horii et al 1998, Bacino et al 2000, Breuning et al 2000, Brunetti-Pierri et al 2010]

The diagnosis of the OPD syndromes is made by a combination of clinical examination, radiologic studies, family history consistent with X-linked inheritance, and molecular genetic testing. Clinical findings are summarized in Tables 1 and 2. Radiologic findings are presented in Table 3.

Molecular Genetic Testing

Gene. FLNA is the only gene in which mutations are known to cause the otopalatodigital (OPD) spectrum disorders.

Clinical testing

• Sequence analysis of entire coding region and of select exons:

Table 4. Summary of Molecular Genetic Testing Used in Otopalatodigital Spectrum Disorders

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Gene Symbol	Test Method	Phenotype	Mutations Detected 1	Mutation Detection Frequency 2, 3	Test Availability
FLNA	Sequence analysis of entire gene 4	OPD1	Missense mutations	94% (n=15)	Clinical
		OPD2	Missense mutations	100% (n=19)
		FMD	Sequence variants 5, 6	68% (n=47) 5
		MNS	Missense mutations	100% (n=27)
		TODPD	Missense mutation c.5217G>A 7	100% (n=6)
	Deletion / duplication analysis 8		Partial- and whole-gene deletions / duplications	Unknown 9

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. Some phenotypes tend to have mutations in specific exons; see Molecular Genetics.

2. The ability of the test method used to detect a mutation that is present in the indicated gene

3. Analysis by mutation scanning of entire gene [Robertson et al 2006b]

4. Some laboratories may offer sequence analysis of select exons.

5. Robertson et al [2006a]

6. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

7. All reported cases of this condition have been shown to be heterozygous for the synonymous change c.5217G>A, which induces a splicing abnormality that results in a loss of 48 bases from the mature transcript and predicts the deletion of 16 amino acids from the resultant FLNA protein (p.Val1724_Thr1739del) [Sun et al 2010]. This mutation appears to define this disorder.

8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. See CMA.

9. Large deletions and duplications have been associated with allelic conditions such as myxomatous cardiac valvular dystrophy (see Genetically Related Disorders) periventricular nodular heterotopia and intellectual disability. Partial- / whole-gene deletions do not cause an OPD spectrum disorder phenotype.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband. Sequence analysis of FLNA should be performed.

Note: Whole-gene deletions cause periventricular nodular heterotopia in females and are likely to be embryonic lethal in males. Partial-gene deletions or duplications have not been associated with OPD spectrum disorders. Whole-gene duplications (in association with neighboring genes) have been associated with intellectual disability and seizures (see Genetically Related Disorders).

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any 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

Periventricular nodular heterotopia, X-linked. This neuronal migration disorder is characterized by the presence of uncalcified nodules of neurons ectopically situated along the surface of the lateral ventricles. Affected individuals are predominantly heterozygous females; males show early lethality. Affected females present with seizures on average at age 14 to 15 years; intelligence ranges from normal to borderline functioning. The risk for stroke and other vascular problems/coagulopathies appears to be increased [Sheen et al 2005].

Loss-of-function mutations spread broadly throughout FLNA are causative [Fox et al 1998, Sheen et al 2001, Parrini et al 2006]; however, there is some bias toward clustering within exons encoding the actin-binding domain of filamin A [Parrini et al 2006]. Germline mutations leading to null alleles are found almost exclusively in females, whereas missense mutations or mosaicism for truncating mutations can account for affected males or a mild phenotype in females [Guerrini et al 2004].

A variant of X-linked periventricular nodular heterotopia with marked connective tissue dysfunction (skin fragility, vascular dilatation) described in females [Sheen et al 2005] has been associated with mutations in FLNA predicted to lead to loss of function [Sheen et al 2005, Gómez-Garre et al 2006, Reinstein et al 2013].

Gastrointestinal dysmotility has long been associated with periventricular nodular heterotopia:

• Several families with the severe gastrointestinal dysmotility phenotype, chronic intestinal pseudo-obstruction and mutations in the 5’ exons of FLNA [Gargiulo et al 2007, Kapur et al 2010] have been described. It is unclear whether periventricular nodular heterotopia cosegregated with intestinal pseudo-obstruction in this family.
• Hehr et al [2006] reported a similar presentation associated with the splice site mutation p.Tyr643Glyfs*39.

One female has been reported with a dual phenotype of periventricular nodular heterotopia and FMD caused by a mutation variably leading to either a substitution or a small deletion as a result of aberrant splicing [Zenker et al 2004].

Myxomatous cardiac valvular dystrophy. Kyndt et al [2007] and Lardeux et al [2011] described this disorder (which is not associated with other neurologic or skeletal manifestations) in four unrelated families in which three missense mutations and a g.10807_12749delinsTG mutation were identified. All mutations lead to substitutions or deletion of amino acids in the most N terminal third of the protein. Of note, cardiac valvular anomalies are associated with X-linked periventricular nodular heterotopia and some OPD spectrum disorders such as frontometaphyseal dysplasia.

Natural History

Little is known about the natural history of the otopalatodigital (OPD) spectrum disorders. All manifestations can begin in childhood in both sexes.

In males, the spectrum of severity ranges from mild manifestations in otopalatodigital syndrome type I (OPD1), to a more severe presentation in frontometaphyseal dysplasia (FMD) and otopalatodigital syndrome type II (OPD2). Prenatal lethality is the most common clinical phenotype in males with Melnick-Needles syndrome (MNS) [Donnenfeld et al 1987].

Females exhibit variable expressivity. In OPD1, females can present with similar severity to affected males. In contrast, some females have only the mildest of manifestations [Gorlin et al 1973]. In OPD2 and FMD, females are less severely affected than related affected males [Fitzsimmons et al 1982, Robertson et al 1997].

Otopalatodigital syndrome type I. Most manifestations are evident at birth. Nothing reported in the literature suggests any late-onset orthopedic complications, reduction in longevity, or reduction in fertility.

Final height can be mildly reduced, but individuals have been characterized with mutations in FLNA and stature greater than the 90th percentile. Pubertal development and intelligence is normal in affected individuals.

Carrier females may develop conductive or neurosensory hearing loss.

Otopalatodigital syndrome type II. Most affected males do not survive beyond the first year of life, usually secondary to thoracic hypoplasia with resulting pulmonary insufficiency.

Males who live beyond the first year of life are usually developmentally delayed and require assistance with feeding and respiratory support.

Frontometaphyseal dysplasia. Males do not experience progression of their skeletal dysplasia but may develop secondary complications of joint contractures. Progressive scoliosis has been described in both males and females. Craniosynostosis can evolve postnatally.

Melnick-Needles syndrome. Substantial variability is observed. Some individuals are diagnosed in adulthood after ascertainment of an affected family member [Kristiansen et al 2002]. Others require substantial respiratory support; several individuals have required ambulatory oxygen supplementation, typically starting in the second decade. Longevity is reduced in these individuals. Occasionally, males can survive the neonatal period but do not typically live beyond the first year of life [Robertson et al 1997, Verloes et al 2000, Santos et al 2010].

The phenotype of one male with a mutation known to lead to conventional MNS in females has been reported. This individual had previously described skeletal (flexed upper limbs, hypoplastic thumbs, post-axial polydactyly, bowed lower limbs, clubfeet, kyphoscoliosis and hypoplastic halluces), craniofacial (large fontanels, malar flattening, bilateral cleft palate, bifid tongue, severe micrognathia) and visceral (fibrosis of pancreas and spleen, bilateral cystic renal dysplasia secondary to obstructive uropathy and omphalocele) findings but unusual ophthalmological signs (exophthalmia, widely spaced eyes, sclerocornea, cataracts, retinal angiomatosis and a cleavage defect of the anterior chambers of both eyes) [Santos et al 2010].

Terminal osseous dysplasia with pigmentary defects. The natural history for females with this condition is not well documented in the literature. A male presentation of TODPD has never been described.

Genotype-Phenotype Correlations

Mutations associated with the OPD spectrum disorders are predicted to maintain the translational reading frame and to produce full-length protein. These mutations are clustered in discrete regions of the gene. Genotype-phenotype correlation is strong. Two large studies have been published to date [Robertson et al 2006a]:

• Otopalatodigital syndrome type I. All males with this diagnosis had mutations in exons 3, 4, or 5.
• Otopalatodigital syndrome type II. All males with this diagnosis had mutations in exons 3, 4, or 5. Females with a phenotype similar to males with typical OPD2 had mutations in exons 28 and 29.
• Frontometaphyseal dysplasia
  • Out of 13 males with FMD, all had mutations in FLNA (exons 3-5, 22, 28-29) [Robertson et al 2006a]. Mutations in females with FMD (found in 68% of affected females) are more widely distributed over the gene (exons 3-5, 11, 22, 28-29, 44-47) than mutations identified in males.
  • One female with a combined FMD-periventricular nodular heterotopia phenotype had a missense mutation that also created an ectopic splice site [Zenker et al 2004].
  • Some mutations are associated with a male-lethal phenotype caused by cardiac and urologic malformations [Stefanova et al 2005, Robertson et al 2006a].
  • No clinical distinction is observed between individuals with FMD and an FLNA mutation and those without such a mutation [Robertson et al 2006a].
• Melnick-Needles syndrome. The vast majority (>90%) of individuals with MNS have mutations in exon 22 of FLNA, with the two preponderant mutations being p.Ala1188Thr and p.Ser1199Leu. Rare individuals have had mutations identified in exons 6 and 23.

Penetrance

Penetrance in males with an FLNA mutation leading to an OPD spectrum disorder is complete.

Some obligate carrier females with FLNA mutations leading to OPD1 have a normal clinical appearance. What proportion of such females have radiographic indicators of their carrier status is not clear.

Anticipation

No evidence suggests genetic anticipation in these disorders.

Nomenclature

The term “otopalatodigital syndrome spectrum disorders” is an umbrella category for four discrete but clinically related conditions, namely: frontometaphyseal dysplasia, Melnick-Needles syndrome (originally referred to as osteodysplasty), otopalatodigital syndrome type I (also called Taybi syndrome after its first description in 1963), and otopalatodigital syndrome type II. The term “spectrum” reflects the fact that, although most individuals can be unambiguously diagnosed with one of the constituent phenotypes, overlapping of the phenotypes has been observed.

Verloes et al [2000] suggested the term "fronto-otopalatodigital osteodysplasia" for the otopalatodigital spectrum disorders, indicative of his prediction that they would prove allelic to one another. This term has not gained acceptance because some of these disorders are clinically discrete, and therefore diagnosis, management, and prognostication are not served by lumping them under one term.

Prevalence

No population-based studies have been performed to assess prevalence adequately.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with otopalatodigital (OPD) spectrum disorders, the following evaluations are recommended:

• Full clinical examination
• Full radiologic skeletal survey
• Audiometry (see Deafness and Hereditary Hearing Loss Overview)
• Ear, nose, and throat examination
• Renal tract ultrasound examination
• Medical genetics consultation

Treatment of Manifestations

• Deafness is managed with hearing aids (see Deafness and Hereditary Hearing Loss Overview). The conductive hearing loss can be caused by fused and misshapen ossicles; attempts to separate the ossicles are usually unsuccessful and can lead to formation of a perilymphatic gusher.
• Stridor in the neonatal period on account of laryngeal stenosis rarely requires surgical intervention and is non-progressive with growth.
• Cosmetic surgery to correct the fronto-orbital deformity has been attempted in some individuals. Re-growth post surgery does not seem to occur [Kung & Sloan 1998]. Hand and foot malformations may also require surgery.
• Orthopedic surgery
  • Surgical correction of limb bowing has not been reported.
  • Several individuals have had scoliosis surgically addressed, with satisfactory results.
  • Chest expansion surgery has been attempted in several individuals with Melnick-Needles syndrome, with only marginal clinical benefit.
• Apnea prevention. Micrognathia and tracheobronchomalacia in severely affected individuals can lead to airway collapse and sleep apnea that have been successfully corrected with continuous positive airway pressure (CPAP) [Lan et al 2006] and mandibular distraction in the most severe instances of MNS.

Prevention of Secondary Complications

Anesthetists should be aware of the associated laryngeal stenosis, if intubation and ventilation are required [Leggett 1988, Mehta & Schou 1988].

Surveillance

Clinical evaluation for development of orthopedic manifestations (e.g., hand contractures in FMD, scoliosis in FMD and MNS) is appropriate. Head size and shape should be monitored as part of the surveillance for evolving craniosynostosis.

Monitoring of hearing loss should be ongoing, as the sensorineural component can be progressive.

Evaluation of Relatives at Risk

Consider molecular genetic testing for the family-specific mutation in all at-risk relatives

Because affected individuals may benefit from early evaluations for hearing loss and orthopedic complications, including scoliosis, molecular genetic testing for the family-specific mutation in all at-risk relatives should be considered.

If molecular genetic testing is not an option for an at-risk child, evaluations for hearing loss and orthopedic complications, including scoliosis, should be instituted as soon as possible after a clinical diagnosis is established in the at-risk relative.

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.

Mode of Inheritance

The otopalatodigital spectrum disorders (OPD spectrum disorders) are inherited in an X-linked manner.

Risk to Family Members — OPD1, OPD2, or Frontometaphyseal Dysplasia (FMD)

Parents of a male proband with OPD1, OPD2, or FMD

The father of an affected male will not have the disease nor will he be a carrier of the mutation.

In a family with more than one affected individual, the mother of an affected male is an obligate carrier.

If pedigree analysis reveals that the proband is the only affected family member, four possible genetic explanations exist:

• The proband has a de novo mutation. In this instance, the proband's mother does not have a gene mutation; and the only other family members at risk are the offspring of the proband. De novo mutations are common in the otopalatodigital spectrum disorders.
• The proband's mother has a de novo mutation. Two types of de novo mutations may be present in the mother:

a.

A de novo germline mutation that was present at the time of her conception, is present in every cell of her body, and is detectable in DNA extracted from her leukocytes

OR

b.

A mutation that is present in some of her germ cells only (termed "germline mosaicism") and is not detectable in DNA extracted from her leukocytes. Germline mosaicism has been reported in otopalatodigital syndrome type I and therefore should be considered in the genetic counseling of at-risk family members [Robertson et al 2006b].

In both instances (a. and b.) each of the proband’s mother’s offspring is at risk of inheriting the mutation; none of the proband’s mother’s sibs, however, is at risk of inheriting the mutation.

• The mother is a carrier and has inherited the disease-causing mutation either from her mother, who has a disease-causing mutation, or from her asymptomatic father, who is mosaic for the mutation.

Parents of a female proband with OPD1, OPD2, or FMD

• If the proband is a female with OPD1, OPD2, or FMD, and if pedigree analysis reveals that she is the only affected family member, it is reasonable to offer molecular genetic testing to both of her parents to determine risks to family members.
• If the proband’s father is asymptomatic, it is possible that he has the mutation in some cells in his body (somatic mosaicism). If her father is asymptomatic and does not have somatic mosaicism for the altered gene, the possible genetic explanations for the origin of the proband’s gene mutation are the same as for a male proband with a negative family history.
• Somatic mosaicism for mutations leading to the OPD spectrum disorders has been described and has the potential to modify the expressivity of these disorders [Robertson et al 2006b].

Sibs of a male proband with OPD1, OPD2, or FMD

• The risk to the sibs of a proband depends on the genetic status of the parents.
• If a parent has an FLNA mutation, the chance of transmitting the mutation in each pregnancy is 50%:
  • When the mother has an FLNA mutation, male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will have a range of possible phenotypic expression.
  • When the father has an FLNA mutation, all female sibs will inherit the mutation; male sibs will not inherit the mutation.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low but greater than that of the general population:
  • If the disease-causing mutation cannot be detected in the DNA of either parent of the proband, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband.
  • Germline mosaicism has been observed in a family with otopalatodigital syndrome type I and is therefore a possibility.

Offspring of a male proband with OPD1, OPD2, or FMD. Males with OPD2 do not reproduce. Males with OPD1 or FMD transmit the disease-causing mutation to all of their daughters and none of their sons.

Offspring of a female proband with OPD1, OPD2, or FMD. Women with an FLNA mutation have a 50% chance of transmitting the disease-causing mutation to each child: sons who inherit the mutation will be affected; daughters will have a range of possible phenotypic expression.

Other family members of a proband with OPD1, OPD2, or FMD. If a parent of the proband is found to also have a disease-causing mutation, his or her female family members may be at risk of having the mutation and being asymptomatic or symptomatic; and his or her male family members may be at risk of being affected depending on their genetic relationship to the proband.

Risk to Family Members — Melnick-Needles Syndrome (MNS) or Terminal Osseous Dysplasia with Pigmentary Skin Defects (TODPD)

Parents of a male proband with MNS

• The father of an affected male will not have the disease nor will he be a carrier of the mutation.
• In a family with affected individuals in more than one generation, the mother of an affected male is an obligate carrier.
• If pedigree analysis reveals that the proband is the only affected family member, four possible genetic explanations exist:
  • The proband has a de novo mutation, in which case the proband's mother does not have a gene mutation. De novo mutations are common in the otopalatodigital spectrum disorders.
  • The proband's mother has a de novo mutation. Two types of de novo mutations may be present in the mother:

    a.

    A germline mutation that was present at the time of her conception. It is present in every cell of her body and is detectable in DNA extracted from her leukocytes
    
    OR

    b.

    A mutation that is present in some of her germ cells only (termed "germline mosaicism") and is not detectable in DNA extracted from her leukocytes. Germline mosaicism has been demonstrated in the otopalatodigital spectrum disorders.
    
    In both instances (a. and b.) each of the proband's mother's offspring is at risk of inheriting the mutation; none of the proband's mother's sibs, however, is at risk of inheriting the mutation.

  • The mother is a carrier and has inherited the disease-causing mutation from her mother who has a disease-causing mutation.

Parents of a female proband with MNS or TODPD. If the proband is a female and if pedigree analysis reveals that she is the only affected family member, it is reasonable to offer molecular genetic testing to her mother to determine risks to family members.

Sibs of a proband with MNS or TODPD

• The risk to the sibs of a proband depends on the genetic status of the mother.
• If the mother has the gene mutation, the chance of transmitting the FLNA mutation in each pregnancy is 50%:
  • Male sibs of a proband with MNS who inherit the mutation will be affected and generally die prenatally or perinatally; female sibs who inherit the mutation will have a range of possible phenotypic expression.
  • Female sibs of a proband with TODPD who inherit the mutation will have a range of possible phenotypic expression.
• When the mother is clinically unaffected, the risk to the sibs of a proband appears to be low but greater than that of the general population:
  • If the disease-causing mutation cannot be detected in the DNA of the mother of the proband, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband.
  • Germline mosaicism has been observed in a female with a mutation leading to otopalatodigital syndrome type I.

Offspring of a male proband with MNS. Males with MNS usually die in the pre- or perinatal period and do not reproduce.

Offspring of a female proband with MNS or TORPD. Women with an FLNA mutation have a 50% chance of transmitting the disease-causing mutation to each child; sons who inherit the mutation will be affected and generally die prenatally; daughters will have a range of possible phenotypic expression.

Carrier Detection

Carrier testing for at-risk family members is available on a clinical basis once the FLNA mutation has been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk.

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

Molecular genetic testing. If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

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

Ultrasound examination. Many of the manifestations of the disorder can be visualized prenatally by ultrasound examination, although the gestational age at which various anomalies can be detected differs. An omphalocele or urinary tract severely dilated by obstruction may be visible from very early in the second trimester. In contrast, the skeletal dysplasia with its associated limb bowing and thoracic hypoplasia may be visible only after 20 weeks' gestation [Eccles et al 1994].

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any 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 filamin class of actin-binding proteins is known to regulate cell stability, protrusion, and motility across various biologic systems [Gorlin et al 1990, Cunningham et al 1992, Ott et al 1998, Leonardi et al 2000, Stahlhut & van Deurs 2000]. Filamin-deficient melanocytes fail to undergo locomotion in response to factors that elicit migration in the same filamin-expressing cells. They exhibit prolonged circumferential blebbing, abnormal phagocytosis, and impaired volume regulation, perhaps secondary to abnormal regulation of sodium channel activity. A similar defect is observed in filamin-deficient macrophages with disruption of myosin during spreading and phagocytosis [Stendahl et al 1980]. Filamin is also required for cell motility and pseudopod formation in the slime mold, Dictyostelium discoideum, suggesting a highly conserved function across species [Cox et al 1996]. A direct mechanism can be drawn with the association of filamin and integrins, which have been implicated in cell adhesion and migration.

The contrast between the phenotypic consequences of loss-of-function mutations (leading to periventricular nodular heterotopia) and those of the clustered missense mutations (leading to the OPD spectrum disorders) is less well understood. Some of these mutations enhance that affinity of filamin A for binding actin. Filamins coordinate and integrate cell signaling and subsequent remodeling of the actin cytoskeleton. The complexity of these integrative functions makes the implication of individual functions in the pathogenesis of these conditions difficult. However, filamin associates with integrins, which regulate such cellular processes as cell adhesion and neuronal migration [Meyer et al 1997, Loo et al 1998, Dulabon et al 2000]. Filamin A may have a similar influence on neuroblast migration during cortical development within the central nervous system. Disruption of this process likely results in the formation of periventricular heterotopias. Similarly, filamins regulate signal transduction by transmembrane receptors and second messengers, the disruption of which could lead to developmental defects such as those observed in the OPD spectrum disorder phenotypes.

Normal allelic variants. As with other loci within Xq28, the level of normal allelic variants in FLNA is low. Several synonymous and nonsynonymous variants have been shown to be present in healthy individuals including some that have been reported in the literature (incorrectly) as causal of disease phenotypes [Masruha et al 2006]. FLNA, which encodes the protein filamin A, encompasses 48 exons spread over 26 kb on chromosome Xq28. The FLNA transcript is 8.3 kb

Pathologic allelic variants. Mutations that lead to the otopalatodigital spectrum disorders are substitutions or small deletions of amino acid residues. These alterations occur in defined regions of the filamin A protein (see Abnormal gene product). Substitutions in the distal portion of the actin-binding domain (termed calponin homology domain 2) lead to OPD1 and OPD2. In contrast, a restricted number of mutations (mostly within exon 22) lead to Melnick-Needles syndrome. Mutations that lead to frontometaphyseal dysplasia are the most widely dispersed, being located in regions that encode the actin binding domain, repeats 3, 9/10, 14/15, and 22/23. This distribution of mutations indicates that very specific functions of filamins are being altered to lead to the OPD spectrum disorders, in contrast to a global loss of function that results in the periventricular nodular heterotopia phenotype.

• OPD1. Sequencing of FLNA will identify mutations in all instances with intense clustering in exons 3-5. Mutations in other exons can be found in instances where the clinical phenotype intersects with FMD.
• OPD2. Sequencing of FLNA will identify most mutations for typical presentations in exons 3-5. Rarely mutations in other exons (11 and 28-29) have been found, especially in instances where female manifestations are more pronounced.
• FMD. FLNA mutations are widespread throughout the gene in individuals with this diagnosis. Therefore, the most efficient approach is to sequence the entire gene with particular attention paid to exons 3-5, 22, 28-29, and 44-47.
• MNS. Nearly all females with this diagnosis have mutations identifiable in exon 22. One mutation has been identified in each of exons 6 and 24.

Normal gene product. Filamin A is a 280-kd filamentous protein comprising 2647 amino acids. The protein links membrane receptors to the actin cytoskeleton and represents a crucial link between signal transduction and the cytoskeleton. The protein consists of an actin-binding domain at the amino terminus, 23 repeats that resemble Ig-like domains and which form a chain-like structure interrupted by two hinge regions, and a C-terminal repeat that undergoes dimerization. There are two principal isoforms of the protein, produced from alternative splicing of exon 32 that encodes a “hinge” domain. Two other filamins, filamin B and filamin C, are encoded by autosomal loci and share significant similarity at the protein level.

Abnormal gene product. Mutations that lead to the otopalatodigital spectrum disorders are predicted to result in filamin A proteins with substitutions or small deletions of amino acid residues. These alterations occur in defined regions of the filamin A. This distribution of mutations indicates that very specific functions of filamins are being altered to lead to the OPD spectrum disorders, in contrast to a global loss of function that results in the periventricular nodular heterotopia phenotype. This pattern of clustered missense mutations suggests that key interactions with filamin or localized domains of filamin that have regulatory functions are altered by these mutations. No specific functions of filamin have been unequivocally linked to the pathogenesis of the OPD spectrum disorders to date.

Literature Cited

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3. Bacino CA, Stockton DW, Sierra RA, Heilstedt HA, Lewandowski R, Van den Veyver IB. Terminal osseous dysplasia and pigmentary defects: clinical characterization of a novel male lethal X-linked syndrome. Am J Med Genet. 2000;94:102–12. [PubMed: 10982966]
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Suggested Reading

1. Feng Y, Chen MH, Moskowitz IP, Mendonza AM, Vidali L, Nakamura F, Kwiatkowski DJ, Walsh CA. Filamin A (FLNA) is required for cell-cell contact in vascular development and cardiac morphogenesis. Proc Natl Acad Sci USA. 2006;103:19836–41. [PMC free article: PMC1702530] [PubMed: 17172441]

Acknowledgments

The author is supported by Curekids New Zealand.

Revision History

• 2 May 2013 (me) Comprehensive update posted live
• 28 April 2009 (cd) Revision: Deletion/duplication analysis available clinically
• 25 July 2008 (me) Comprehensive update posted live
• 30 November 2005 (me) Review posted to live Web site
• 14 March 2005 (sr) Original submission