Clinical characteristics.

The X-linked otopalatodigital (X-OPD) spectrum disorders, characterized primarily by skeletal dysplasia, include the following:

• Otopalatodigital syndrome type 1 (OPD1)
• Otopalatodigital syndrome type 2 (OPD2)
• Frontometaphyseal dysplasia type 1 (FMD1)
• Melnick-Needles syndrome (MNS)
• Terminal osseous dysplasia with pigmentary skin defects (TODPD)

In OPD1, most manifestations are present at birth; females can present with severity similar to affected males, although some have only mild manifestations. In OPD2, females are less severely affected than related affected males. Most males with OPD2 die during the first year of life, usually from thoracic hypoplasia resulting in pulmonary insufficiency. Males who live beyond the first year of life are usually developmentally delayed and require respiratory support and assistance with feeding. In FMD1, females are less severely affected than related affected males. Males do not experience a progressive skeletal dysplasia but may have joint contractures and hand and foot malformations. Progressive scoliosis is observed in both affected males and females. In MNS, wide phenotypic variability is observed; some individuals are diagnosed in adulthood, while others require respiratory support and have reduced longevity. MNS in males results in perinatal lethality in all recorded cases. TODPD, seen only in females, is characterized by a skeletal dysplasia that is most prominent in the digits, pigmentary defects of the skin, and recurrent digital fibromata.

Diagnosis/testing.

The diagnosis of an X-OPD spectrum disorder is established in a male proband with characteristic clinical and radiographic features and a family history consistent with X-linked inheritance. Identification of a hemizygous pathogenic variant in FLNA by molecular genetic testing can confirm the diagnosis if clinical features, radiographic features, and/or family history are inconclusive.

The diagnosis of an X-OPD spectrum disorder is usually established in a female proband with characteristic clinical and radiographic features and a family history consistent with X-linked inheritance. Identification of a heterozygous pathogenic variant in FLNA by molecular genetic testing can confirm the diagnosis if clinical features, radiographic features, and/or family history are inconclusive.

Management.

Treatment of manifestations: Surgical treatment may be required for hand and foot malformations. Monitoring and surgical intervention as needed for scoliosis; physiotherapy for contractures; cosmetic surgery may correct the fronto-orbital deformity; continuous positive airway pressure (CPAP) and mandibular distraction can improve airway complications related to micrognathia; hearing aids for deafness; evaluation with anesthesiology if intubation and ventilation are required due to laryngeal stenosis.

Surveillance: Annual clinical evaluation for orthopedic complications including contractures and scoliosis; monitor head size and shape with each clinical evaluation in infancy for craniosynostosis; annual clinical evaluation for apnea with somnography studies as indicated; annual audiology evaluation.

Evaluation of relatives at risk: Consider molecular genetic testing for the family-specific pathogenic variant in at-risk relatives.

Genetic counseling.

The X-OPD spectrum disorders are by definition inherited in an X-linked manner. If a parent of a proband with OPD1, OPD2, or FMD1 has the FLNA pathogenic variant, the chance of transmitting the variant in each pregnancy is 50%.

• When the mother has an FLNA pathogenic variant, males who inherit the variant will be affected; females who inherit the variant have a range of phenotypic expression. If the mother of a proband with TODPD or MNS has the FLNA pathogenic variant, the chance of transmitting the variant in each pregnancy is 50%. Males who inherit the variant will be affected and usually exhibit embryonic lethality or die perinatally (MNS); females who inherit the variant have a range of phenotypic expression.
• Males with OPD2 do not reproduce; males with OPD1 or FMD1 transmit the pathogenic variant to all of their daughters and none of their sons.

Prenatal testing and preimplantation genetic testing are possible if the pathogenic variant in the family is known.

Suggestive Findings

X-OPD spectrum disorders should be suspected in an individual with the following clinical (Table 1) and radiographic (Table 2) features.

Establishing the Diagnosis

Male proband. The diagnosis of an X-OPD spectrum disorder is established in a male proband with characteristic clinical (Table 1) and radiographic (Table 2) features and a family history consistent with X-linked inheritance. Identification of a hemizygous pathogenic variant in FLNA by molecular genetic testing can confirm the diagnosis if clinical features, radiographic features, and/or family history are inconclusive (see Table 3).

Female proband. The diagnosis of an X-OPD spectrum disorder is usually established in a female proband with characteristic clinical (Table 1) and radiographic (Table 2) features and a family history consistent with X-linked inheritance. Identification of a heterozygous pathogenic variant in FLNA by molecular genetic testing can confirm the diagnosis if clinical features, radiographic features, and/or family history are inconclusive (see Table 3).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of X-OPD spectrum disorders is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of an X-OPD spectrum disorder has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

To date, more than 150 individuals with an X-OPD syndrome spectrum disorder have been identified with a pathogenic variant in FLNA [Robertson et al 2003, Robertson et al 2006a, Robertson et al 2006b]. The following description of the phenotypic features associated with this condition is based on these reports.

Little is known about the natural history of the X-linked otopalatodigital (X-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 1 (OPD1) to a more severe presentation in frontometaphyseal dysplasia type 1 (FMD1) and otopalatodigital syndrome type 2 (OPD2). Prenatal lethality is the only clinical phenotype described in males with Melnick-Needles syndrome (MNS) [Spencer et al 2018].

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 FMD1, females are less severely affected than related affected males [Robertson et al 1997, Moutton et al 2016].

Genotype-Phenotype Correlations

Pathogenic variants associated with the X-OPD spectrum disorders are predicted to maintain the translational reading frame and to produce full-length protein. These variants 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]:

• OPD1. All males with this diagnosis had pathogenic variants in exons 3, 4, or 5.
• OPD2. All males with this diagnosis had pathogenic variants in exons 3, 4, or 5. Females with a phenotype similar to males with typical OPD2 had pathogenic variants in exons 28 and 29.
• Frontometaphyseal dysplasia
  • Out of 13 males with FMD1, all had pathogenic variants in FLNA (exons 3-5, 22, 28-29) [Robertson et al 2006a]. Pathogenic variants in females with FMD1 (found in 68% of affected females) are more widely distributed over the gene (exons 3-5, 11, 22, 28-29, 41, 44-47) than pathogenic variants identified in males.
  • One female with a combined FMD1-periventricular nodular heterotopia phenotype had a missense variant that also created an ectopic splice site [Zenker et al 2004].
  • Some pathogenic variants are associated with a male-lethal phenotype caused by cardiac and urologic malformations [Stefanova et al 2005, Robertson et al 2006a].
• Melnick-Needles syndrome. The vast majority (>90%) of individuals with MNS have pathogenic variants in exon 22 of FLNA, with the two preponderant variants being p.Ala1188Thr and p.Ser1199Leu. Rare individuals have had pathogenic variants identified in exons 6 and 23.

Penetrance

Penetrance in males with an FLNA pathogenic variant leading to an X-OPD spectrum disorder is complete.

Some obligate heterozygote females with FLNA pathogenic variants leading to OPD1 have a normal clinical appearance. The proportion of heterozygous females with radiographic features of OPD1 is unknown

Nomenclature

Melnick-Needles syndrome was originally referred to as osteodysplasty.

OPD1 was also called Taybi syndrome after its first description in 1963.

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

Prevalence

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

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an X-linked otopalatodigital (X-OPD) spectrum disorder, the evaluations summarized in Table 6 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early evaluations for hearing loss and orthopedic complications, including scoliosis.

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

Mode of Inheritance

The X-linked otopalatodigital (X-OPD) spectrum disorders – otopalatodigital syndrome type 1 (OPD1), otopalatodigital syndrome type 2 (OPD2), frontometaphyseal dysplasia type 1 (FMD1), Melnick-Needles syndrome (MNS), and terminal osseous dysplasia with pigmentary skin defects (TODPD) – are inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disorder nor will he be hemizygous for the FLNA pathogenic variant.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the FLNA pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. Germline mosaicism has been reported in X-OPD spectrum disorders [Robertson et al 2006b].
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a de novo FLNA pathogenic variant, in which case the mother is not a carrier. De novo pathogenic variants are common in X-OPD spectrum disorders.

Parents of a female proband

• A female proband may have inherited the FLNA pathogenic variant from either her mother or her father, or the pathogenic variant may be de novo.
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a de novo pathogenic variant from those with an inherited pathogenic variant. Molecular genetic testing of the mother (and possibly the father, or subsequently the father) can determine if the pathogenic variant was inherited.
  Note: If a female proband's father is asymptomatic, it is possible that he has the pathogenic variant in some cells in his body (somatic mosaicism). Somatic mosaicism for pathogenic variants leading to the X-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. The risk to sibs depends on the genetic status of the mother:

• If the mother of the proband has a FLNA pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
  • Males who inherit the pathogenic variant will be affected. Note: Male sibs of a proband with MNS or TODPD who inherit the pathogenic variant will be affected and generally die prenatally or perinatally.
  • Females who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the FLNA pathogenic variant cannot be detected in the leukocyte DNA of the mother, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Robertson et al 2006b].

Sibs of a female proband. The risk to sibs depends on the genetic status of the parents:

• If the mother of the proband has an FLNA pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
  • Males who inherit the pathogenic variant will be affected. Note: Male sibs of a proband with MNS or TODPD who inherit the pathogenic variant will be affected and generally die prenatally or perinatally.
  • Females who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations.
• If the father of the proband has an FLNA pathogenic variant, he will transmit it to all his daughters and none of his sons.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the FLNA pathogenic variant cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Robertson et al 2006b].

Offspring of a male proband

• Males with OPD1 or FMD1 transmit the pathogenic variant to all of their daughters and none of their sons.
• Males with OPD2 do not reproduce.
• Males with MNS usually die in the pre- or perinatal period and do not reproduce.

Offspring of a female proband. Females who are heterozygous for an FLNA pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the FLNA pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating 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/preimplantation genetic 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the FLNA pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for an X-OPD spectrum disorder are possible.

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 [Naudion et al 2016].

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

FLNA encodes filamin A, a member of the class of actin-binding proteins that regulate cell stability, protrusion, and motility across various organisms [Gorlin et al 1990, Cunningham et al 1992]. Filamins coordinate and integrate cell signaling and subsequent remodeling of the actin cytoskeleton. 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]. The complexity of these interactions makes the implication of individual functions in the pathogenesis of these conditions difficult. Structural mechanisms that change the topology of filamin in such circumstances – and possibly alter binding interactions or post-translational modification of filamin as a result – have been described.

Filamin A may influence neuroprogenitor differentiation and migration during cortical development within the central nervous system via its interaction with the cytoskeleton. Disruption of this process could result in the formation of periventricular heterotopia [Carabalona et al 2012]. 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 X-linked otopalatodigital (X-OPD) spectrum disorder phenotypes.

Mechanism of disease causation. The mechanism of disease for loss-of-function variants (leading to periventricular nodular heterotopia) and of the clustered pathogenic missense variants (leading to the X-OPD spectrum disorders) are not fully understood.

This clustered distribution of pathogenic missense variants that lead to the X-OPD spectrum disorders indicates that very specific functions of filamins are being altered. Interactions with filamin or localized domains of filamin that have regulatory functions may be altered by these pathogenic variants. Some missense variants enhance the affinity of filamin A for binding actin [Clark et al 2009] while others alter the mechanically sensitive properties of filamin [Ithychanda et al 2017].

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Acknowledgments

The author is supported by Curekids New Zealand.

Revision History

• 3 October 2019 (sw) Comprehensive update posted live
• 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 live
• 14 March 2005 (sr) Original submission