Clinical characteristics.

The FLNA-related otopalatodigital (FLNA-OPD) spectrum disorders, characterized primarily by skeletal dysplasia, include the following allelic conditions: otopalatodigital syndrome type 1 (FLNA-OPD1), otopalatodigital syndrome type 2 (FLNA-OPD2), frontometaphyseal dysplasia (FLNA-FMD), Melnick-Needles syndrome (FLNA-MNS), and terminal osseous dysplasia (FLNA-TOD). In FLNA-OPD1, most manifestations are present at birth; females can present with severity similar to affected males, although some have only mild manifestations. In FLNA-OPD2, females are less severely affected than related affected males. Most males with FLNA-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 FLNA-FMD, females are less severely affected than related affected males who are hemizygous for the same allele. Males usually, but not always, demonstrate a skeletal dysplasia in association with hearing loss and, variably, joint contractures and hand and foot malformations. Progressive scoliosis is observed in both affected males and females. In females with FLNA-MNS, wide phenotypic variability is observed; some individuals are diagnosed in adulthood, while others require respiratory support and have reduced longevity. FLNA-MNS in males results in perinatal lethality in all known individuals. FLNA-TOD, seen only in females, is characterized by a skeletal dysplasia that is most prominent in the hand and feet, pigmentary defects of the skin, and recurrent digital fibromata.

Diagnosis/testing.

The diagnosis of an FLNA-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 FLNA-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, bracing, and surgical intervention as needed for scoliosis; physical therapy for contractures; cosmetic surgery may correct the fronto-orbital deformity; surgical correction for orthognathic deformities as needed; chest expansion surgery has been used to treat thoracic hypoplasia; continuous positive airway pressure and mandibular distraction can improve airway complications related to micrognathia; hearing aids for deafness; treatment of cardiac anomalies and cardiomyopathy per cardiologist and cardiac surgeon; treatment of oligohypodontia per orthodontist and/or dental surgeon; treatment of genitourinary anomalies per urologist; evaluation with anesthesiologist if intubation and ventilation are required due to laryngeal stenosis.

Surveillance: Annual clinical evaluation for orthopedic complications including contractures and scoliosis; evaluation of bone mineral density in those with FLNA-FMD; monitor head size and shape with each clinical evaluation in infancy for craniosynostosis; annual clinical evaluation for apnea with polysomnography studies as indicated; annual audiology evaluation; dental evaluations every six to 12 months beginning with eruption of primary teeth.

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

Genetic counseling.

FLNA-OPD spectrum disorders are inherited in an X-linked manner. 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. Penetrance in males with an FLNA pathogenic variant leading to an FLNA-OPD spectrum disorder is complete (male sibs of a proband with FLNA-MNS or FLNA-TOD 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. Once the FLNA pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for FLNA-OPD spectrum disorders are possible.

Suggestive Findings

FLNA-OPD spectrum disorders should be suspected in an individual with the following clinical features (see Table 1), radiographic features (see Table 2), and family history.

Family history is consistent with X-linked inheritance (e.g., no male-to-male transmission). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

Male proband. The diagnosis of an FLNA-OPD spectrum disorder is established in a male proband with characteristic clinical (see Table 1) and radiographic (see Table 2) features and a family history consistent with X-linked inheritance. Identification of a hemizygous pathogenic (or likely 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 FLNA-OPD spectrum disorder is usually established in a female proband with characteristic clinical (see Table 1) and radiographic (see Table 2) features and a family history consistent with X-linked inheritance. Identification of a heterozygous pathogenic (or likely 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).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a hemizygous or heterozygous FLNA variant of uncertain significance does not establish or rule out the diagnosis.

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). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

The FLNA-related otopalatodigital (FLNA-OPD) spectrum disorders, characterized primarily by skeletal dysplasia, include the following allelic conditions: otopalatodigital syndrome type 1 (FLNA-OPD1), otopalatodigital syndrome type 2 (FLNA-OPD2), frontometaphyseal dysplasia type 1 (FLNA-FMD), Melnick-Needles syndrome (FLNA-MNS), and terminal osseous dysplasia (FLNA-TOD). To date, more than 500 individuals with an FLNA-OPD spectrum disorder have been identified [Robertson et al 2003, Robertson et al 2006a, Robertson et al 2006b, Moutton et al 2016, Naudion et al 2016, Wade et al 2020]. The following description of the phenotypic features associated with this condition is based on these reports.

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

In males, the spectrum of severity ranges from mild manifestations in FLNA-OPD1 to a more severe presentation in FLNA-FMD and FLNA-OPD2. Prenatal or perinatal lethality with multiple congenital malformations is the only clinical phenotype described in males with FLNA-MNS [Spencer et al 2018].

Females exhibit variable expressivity. In FLNA-OPD1, females can present with similar severity to affected males or with only mild manifestations [Gorlin et al 1973]. In FLNA-OPD2 and FLNA-FMD, females are less severely affected than related affected males [Robertson et al 1997, Moutton et al 2016].

Genotype-Phenotype Correlations

Pathogenic variants associated with FLNA-OPD spectrum disorders are predicted to maintain the translational reading frame of FLNA and to produce full-length protein. These variants are clustered in discrete regions of the gene. Genotype-phenotype correlation is strong [Robertson et al 2006a, Wade et al 2020]. The clinical presentation and position of the FLNA pathogenic variant can often broadly predict the phenotype. For example, MNS due to recurrent variants in exon 22 of FLNA are invariably associated with prenatal lethality in males; pathogenic variants in FLNA exons 2-4, associated with an FMD phenotype in females, are consistent with male survival. However, not all individuals can be classified with a discrete clinical phenotype, and occasionally individuals exhibit intermediate phenotypes that bridge FLNA-OPD1 and FLNA-FMD, FLNA-OPD1 and FLNA-OPD2, and FLNA-FMD and FLNA-MNS.

• FLNA-OPD1. All males with a phenotype that includes the characteristic acral patterning malformation in the feet and hands have pathogenic variants in exons 3, 4, or 5.
• FLNA-OPD2. All males with a diagnosis of FLNA-OPD2 have pathogenic variants in exons 3, 4, or 5. Occasional reports of females with a phenotype similar to males with typical FLNA-OPD2 have pathogenic variants in exons 28 and 29; the severity of the phenotype in these females possibly predicts a male embryonic-lethal phenotype.
• FLNA-FMD
  • Variants leading to FLNA-FMD are broadly dispersed in regions of FLNA [Wade et al 2020] including exons 3-5, 22, 28-35, and 41-47. Occasional individuals have pathogenic variants lying outside these regions [Moutton et al 2016].
  • In a study of 13 males with FLNA-FMD, all had pathogenic variants in exons 3-5, 22, or 28-29 [Robertson et al 2006a]. Pathogenic variants in females with FLNA-FMD (reported in 68% of affected females) are more widely distributed across the gene (exons 3-5, 22, 28-35, 41-47) than pathogenic variants identified in males.
  • One female with a combined FMD-periventricular nodular heterotopia phenotype had an FLNA missense variant that also created an ectopic splice site resulting in combined gain and loss of function [Zenker et al 2004]. Similarly, four females (from two families) were reported with a combined FMD-periventricular nodular heterotopia phenotype due to a FLNA pathogenic variant p.Gly208Arg that also led to both gain and loss of function.
  • Some pathogenic variants are associated with severe male phenotypes including cardiac and urologic malformations [Stefanova et al 2005, Robertson et al 2006a, Iqbal et al 2020]. Affected individuals with FLNA-FMD from one family had a strong predominance of Ebstein anomaly in addition to other milder cardiac valvular dysplasia caused by a missense variant predicted to result in p.Gly1554Arg [Mercer et al 2017].
• FLNA-MNS. The vast majority (>90%) of individuals with FLNA-MNS have pathogenic variants in exon 22, with the two preponderant variants being p.Ala1188Thr and p.Ser1199Leu. Rare individuals have had pathogenic variants identified in exons 6 and 23. Numerous case reports of individuals with a diagnosis of FLNA-MNS based on limb bowing and cortical irregularity are more adequately diagnosed with FLNA-FMD, since their phenotype is more attenuated and male survival has been demonstrated.

Penetrance

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

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

Nomenclature

MNS was originally referred to as osteodysplasty.

OPD1 was also referred to as Taybi syndrome after its first description in 1963.

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 FLNA-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

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 7).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 8 are recommended.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk female 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

FLNA-related otopalatodigital (FLNA-OPD) spectrum disorders are inherited in an X-linked manner and include the following phenotypes:

• Otopalatodigital syndrome type 1 (FLNA-OPD1)
• Otopalatodigital syndrome type 2 (FLNA-OPD2)
• Frontometaphyseal dysplasia (FLNA-FMD)
• Melnick-Needles syndrome (FLNA-MNS)
• Terminal osseous dysplasia (FLNA-TOD)

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; therefore, he does not require further evaluation/testing.
• 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 gonadal mosaicism. Gonadal mosaicism has been reported in FLNA-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, the affected male may have a de novo FLNA pathogenic variant (in which case the mother is not a heterozygote), or the mother may have somatic/gonadal mosaicism [Robertson et al 2006b]. De novo pathogenic variants are common in FLNA-OPD spectrum disorders.
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.

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: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• 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 FLNA-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 an FLNA pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
  • Males who inherit the pathogenic variant will be affected. Penetrance in males with an FLNA pathogenic variant leading to an FLNA-OPD spectrum disorder is complete. Note: Male sibs of a proband with FLNA-MNS or FLNA-TOD 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. Females with:
    • FLNA-OPD1 exhibit variable expressivity;
    • FLNA-OPD2 usually present with a subclinical phenotype;
    • FLNA-FMD present with characteristic but milder craniofacial features similar to those of affected males;
    • FLNA-MNS present with substantial clinical variability;
    • FLNA-TOD exhibit pronounced abnormalities of the face, hands, and skin.
• If the proband represents a simplex case 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 maternal gonadal 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 (see Sibs of a male proband).
  • Females who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations (see Sibs of a male proband).
• If the father of the proband has an FLNA pathogenic variant, he will transmit it to all of his daughters and none of his sons.
• If the proband represents a simplex case 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 gonadal mosaicism [Robertson et al 2006b].

Offspring of a male proband

• Males with FLNA-OPD1 or FLNA-FMD transmit the pathogenic variant to all of their daughters and none of their sons.
• Males with FLNA-OPD2 are not known to reproduce.
• Males with FLNA-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, the parent's 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 or are at risk of having an FLNA pathogenic variant.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the FLNA pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for FLNA-OPD spectrum disorders 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 acral patterning defects, 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 and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic 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 has been proposed to be a sensor of mechanical force, both during development but also during physiologic functions carried out by a mobile organism operating in a gravitational environment. Domains of filamin-A integral to this could be those involved with engagement with the actin cytoskeleton mediated by the N-terminal actin-binding domain, the hinge-1 region, and filamin protein repeats 14-16 and 19-21. These regions of the protein correspond to the sites of causal pathogenic variants of FLNA-related otopalatodigital (FLNA-OPD) spectrum disorders.

Mechanism of disease causation. The clustered distribution of pathogenic missense variants that cause FLNA-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 pathogenic variants lead to phenotypes with mild or negligible skeletal manifestations [Wade et al 2021], while nearby pathogenic variants produce phenotypes that demonstrate florid osteosclerosis [Ithychanda et al 2017]. These observations suggest regions of filamin-A that mediate mechanical signaling function differentially across tissues. 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 [Seppälä et al 2017]; attempts to replicate this mechanism in mouse models have not met with success [Wade et al 2024a].

Author Notes

Stephen Robertson is Director of the Laboratory for Genomic Medicine at the University of Otago in Dunedin, New Zealand.

Both Stephen Robertson (zn.ca.ogato@nostrebor.nehpets) and Emma Wade (zn.ca.ogato@edaw.amme) are actively involved in clinical research regarding individuals with X-linked filaminopathies and FLNA-related loss-of-function disorders. They would be happy to communicate with persons who have any questions regarding diagnosis of individuals or families with phenotypes within either of these categories, variants in FLNA that might be of diagnostic significance, or other related considerations. Additionally, both authors are also interested in hearing from clinicians treating families affected by phenotypes similar to those seen in FLNA-related disorders in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Acknowledgments

The authors are supported by Curekids New Zealand (SR), the Marsden Fund of New Zealand (SR), and the Health Research Council of New Zealand (SR, EW).

Revision History

• 26 June 2025 (sw) Comprehensive update posted live
• 3 October 2019 (sw) Comprehensive update posted live
• 2 May 2013 (me) Comprehensive update posted live
• 25 July 2008 (me) Comprehensive update posted live
• 30 November 2005 (me) Review posted live
• 14 March 2005 (sr) Original submission

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