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Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.

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X-Linked Otopalatodigital Spectrum Disorders

Synonym: Otopalatodigital Spectrum Disorders (OPDSD)

, FRACP, DPhil.

Author Information

Initial Posting: ; Last Update: October 3, 2019.

Estimated reading time: 27 minutes

Summary

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 diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known.

GeneReview Scope

X-Linked Otopalatodigital Spectrum Disorders: Included Phenotypes 1
  • 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)

For synonyms and outdated names see Nomenclature.

1.

For other genetic causes of these phenotypes see Differential Diagnosis.

Diagnosis

The X-linked otopalatodigital (X-OPD) spectrum disorders, a heterogeneous group of disorders characterized primarily by a skeletal dysplasia of variable severity, 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)

Suggestive Findings

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

Table 1.

X-Linked Otopalatodigital Spectrum Disorders: Clinical Features

PhenotypeCraniofacial FeaturesSkeletal FeaturesOther
OPD1
(male
phenotype)
Cleft palate & characteristic facies: prominent supraorbital ridges, downslanted palpebral fissures, hypertelorism, broad nasal bridge & nasal tip, hypodontia, oligodontiaDigits: short proximally placed thumbs, hypoplastic distal phalanges, great toe hypoplasia, long 2nd toe, prominent sandal gap; limited joint mobility; limbs w/mild bowingConductive & sensorineural hearing loss; normal intelligence
Heterozygous females 1: variable features; some females as affected as male relatives.
OPD2
(male
phenotype)
Pierre Robin sequence; characteristic facies (more severe than OPD1)Digits: hypoplastic thumbs & great toes, absent halluces, camptodactyly; thoracic hypoplasia; delayed closure of fontanelles; bowed limbs; short statureConductive & SNHL; cardiac: septal defects, obstructive lesions to the right ventricular outflow tract; omphalocele; GU: ureteric obstruction w/hydronephrosis, hypospadias; CNS: hydrocephalus, cerebellar hypoplasia; DD; death in neonatal period
Heterozygous females 1: often subclinical phenotype; characteristic facies (prominent supraorbital ridges, wide nasal bridge & broad nasal tip) are most common findings. Occasionally conductive HL, cleft palate, skeletal & digital anomalies.
FMD1
(male
phenotype)
Characteristic facies (more severe than OPD2)Digits: distal phalangeal hypoplasia, progressive contractures of the hands; limited joint mobility (wrists, elbows, knees, ankles); scoliosis; bowed limbsConductive & SNHL; underdevelopment of musculature (shoulder girdle, intrinsic muscles of the hands); subglottic stenosis w/congenital stridor; GU: ureteric & urethral stenosis, hydronephrosis; normal intelligence
Heterozygous females: characteristic facies similar to affected males
MNS
(female
phenotype)
Prominent lateral margins of the supraorbital ridges, proptosis, full cheeks, micrognathia, oligohypodontia, facial asymmetryDigits: long w/mild distal phalangeal hypoplasia; thoracic hypoplasia; bowed limbs; joint subluxation; short statureConductive & SNHL; ureteric obstruction w/hydronephrosis; coloboma; normal intelligence
Hemizygous males: phenotype ranges from lethal phenotype similar to severe OPD2 to mildly affected.
TODPD
(female
phenotype)
Widely spaced eyes, oral frenulae, hyperpigmented lesions over the temporal region, alopeciaDigits: fibromata in infancy, camptodactyly; bowed limbs; short statureCardiac: septal defects; normal intelligence
Hemizygous males: phenotype has not been described in males.

DD = developmental delay; FMD1 = frontometaphyseal dysplasia type 1; GU = genitourinary; MNS = Melnick-Needles syndrome; OPD1 = otopalatodigital syndrome type 1; OPD2 = otopalatodigital syndrome type 2; SNHL = sensorineural hearing loss; TODPD = terminal osseous dysplasia with pigmentary skin defects

1.

OPD1 and OPD2 cannot be clinically differentiated in a single affected female in a family with no affected males.

Table 2.

X-Linked Otopalatodigital Spectrum Disorders: Radiographic Features

PhenotypeSkullSpineThoraxLong BonesHands / FeetPelvis
OPD1
(male phenotype)
Sclerosis of skull base; thickened calvarium; underdeveloped frontal sinuses; mastoids under-pneumatizedFailure of fusion of posterior vertebral arches (especially cervical)Mild bowing; dislocation of radial headsThumb w/short, broad metacarpal; distal phalangeal hypoplasia; accessory proximal ossification center of 2nd metacarpal; accessory carpal bones; fusion of carpal & tarsal bonesContracted; no iliac flaring
OPD2
(male phenotype)
Same as OPD1; large fontanellesSame as OPD1; segmentation anomaliesHypoplastic; thin ribsBowed; splayed metaphyses; absent fibulaeBroad, poorly modeled phalanges, metacarpals & metatarsals; ± duplicated terminal phalangesSame as OPD1
FMD1
(male phenotype)
Same as OPD1; occasionally, craniosynostosisFusion of C2-3-4; deficiency of posterior vertebral arches± coat-hanger shape ribsMild bowing; undertubulationCarpal & tarsal fusions; later erosion of carpal bones; elongation, poor modeling of phalanges, metacarpals & metatarsals; distal phalangeal hypoplasia (thumbs & great toes)
MNS
(female phenotype)
Same as OPD1↑ vertebral body height, especially lumbar; scoliosisHypoplasia; ribs irregular; wavy clavicle w/expansion of proximal endBowed, sometimes ribbon-like; cortical irregularityElongation & undermodeling of phalanges, metacarpals & metatarsalsSupra-acetabular constriction; iliac flaring
TODPD
(female phenotype)
NormalScoliosisNo abnormalities consistently describedIrregular ossification; cystic lesions near epiphyses; bowed; radial head dislocationHypoplasia, shortening, irregular ossification &/or fusions of carpals & metacarpals; irregular corticesNarrow ilia; coxa vara

FMD1 = frontometaphyseal dysplasia type 1; MNS = Melnick-Needles syndrome; OPD1 = otopalatodigital syndrome type 1; OPD2 = otopalatodigital syndrome type 2; TODPD = terminal osseous dysplasia with pigmentary skin defects

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).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of an X-OPD spectrum disorder, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Perform sequence analysis of FLNA to detect small intragenic deletions/insertions and missense variants.
    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 X-OPD spectrum disorders. Whole-gene duplications (in association with neighboring genes) have been associated with intellectual disability and seizures (see Genetically Related Disorders).
    Targeted analysis for variant c.5217G>A can be performed first in individuals with a phenotype suggestive of TODPD; however, this test is not exclusionary for TODPD.
  • A multigene panel that includes FLNA and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the diagnosis of an X-OPD spectrum disorder is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 3.

Molecular Genetic Testing Used in X-Linked Otopalatodigital Spectrum Disorders

Gene 1MethodPhenotypeProportion of Probands with a Pathogenic Variant 2 Detectable by Method
FLNASequence analysis 3OPD194% (n=15) 4
OPD2100% (n=19) 4
FMD171% (n=47) 5
MNS100% (n=27) 4
Targeted analysis for c.5217G>ATODPD100% (n=6) 6
Gene-targeted deletion/duplication analysis 7None 8

FMD1 = frontometaphyseal dysplasia type 1; MNS = Melnick-Needles syndrome; OPD1 = otopalatodigital syndrome type 1; OPD2 = otopalatodigital syndrome type 2; TODPD = terminal osseous dysplasia with pigmentary skin defects

1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.
6.

All reported individuals with TODPD have been 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 pathogenic variant appears to define this disorder.

7.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

8.

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- and whole-gene deletions do not cause an X-OPD spectrum disorder phenotype.

Clinical Characteristics

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.

Table 4.

Features of X-Linked Otopalatodigital Spectrum Disorders

DisorderFeatures% of Persons with Feature
OPD1 in malesDigital anomalies100%
Deafness100%
Mild limb bowingUnknown
Cleft Palate75%
OPD2 in malesThoracic hypoplasia100%
Cleft palate80%
FMD1 in malesSupraorbital hyperostosis100%
Urinary Tract obstructionUnknown
MNS in femalesMicrognathia100%
Limb bowing100%
Short stature100%
Thoracic hypoplasia100%
TODPD in femalesDigital fibromata100%
Erosive changes on radiographs100%
Limb bowingUnknown

FMD1 = frontometaphyseal dysplasia type 1; MNS = Melnick-Needles syndrome; OPD1 = otopalatodigital syndrome type 1; OPD2 = otopalatodigital syndrome type 2; TODPD = terminal osseous dysplasia with pigmentary skin defects

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].

OPD1

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

Males with OPD1 present with the following:

  • A skeletal dysplasia manifest clinically by:
    • Digital anomalies including short, often proximally placed thumbs with hypoplasia of the distal phalanges. The distal phalanges of the other digits can also be hypoplastic with a squared (or "spatulate") disposition to the finger tips. The toes present a characteristic pattern of hypoplasia of the great toe, a long second toe, and a prominent sandal gap.
    • Limitation of joint movement (elbow extension, wrist abduction) in almost all affected individuals
    • Limbs that may exhibit mild bowing
    • Mildly reduced final height in some, although individuals have been characterized with pathogenic variants in FLNA and stature greater than the 90th percentile. Pubertal development and intelligence is normal in affected individuals.
  • Characteristic facial features (prominent supraorbital ridges, downslanted palpebral fissures, widely spaced eyes, wide nasal bridge and broad nasal tip)
  • Deafness (secondary either to ossicular malformation, neurosensory deficit, or a combination of both). 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.
  • Cleft palate
  • Oligohypodontia
  • Normal intelligence

Females with OPD1 exhibit variable expressivity. Some females can manifest a phenotype similar to that of affected, related males. Females may develop conductive or neurosensory hearing loss. Note: One cannot confidently differentiate OPD1 from OPD2 in a single affected female in a family with no affected males [Moutton et al 2016].

OPD2

Males with OPD2 present with the following [André et al 1981, Fitch et al 1983]:

  • A skeletal dysplasia manifest clinically as:
    • Thoracic hypoplasia
    • Bowed long bones
    • Short stature
    • Digital anomalies (most commonly: hypoplasia of the first digit of the hands and feet or absent halluces, camptodactyly)
    • Delayed closure of the fontanelles
    • Scoliosis (occasional)
  • Characteristic craniofacial features similar to but more pronounced than those in OPD1. Pierre Robin sequence is commonly observed.
  • Sensorineural and conductive deafness (common)
  • Cardiac septal defects and obstructive lesions to the right ventricular outflow tract in some affected individuals
  • Associated omphalocele, hydronephrosis secondary to ureteric obstruction, and hypospadias [Young et al 1993, Robertson et al 1997]
  • Central nervous system anomalies including hydrocephalus, cerebellar hypoplasia, and (rarely) encephalocele and meningomyelocele [Brewster et al 1985, Stratton & Bluestone 1991]
  • Developmental delay (common)
  • Death commonly in the neonatal period as a result of respiratory insufficiency. Survival into the third year of life has been described with intensive medical treatment [Verloes et al 2000].

Females with OPD2 usually present with a subclinical phenotype. Characteristic craniofacial features (prominent supraorbital ridges, wide nasal bridge and a broad nasal tip) are the most common findings. Occasionally, conductive hearing loss has been described. Occasionally, females can manifest a phenotype similar in severity to that of males (craniofacial dysmorphism, cleft palate, conductive hearing loss, skeletal and digital anomalies). Note: One cannot confidently differentiate OPD1 from OPD2 in a single affected female in a family with no affected males.

Frontometaphyseal Dysplasia Type 1

Frontometaphyseal dysplasia type 1 (FMD1) shares many characteristics with OPD1, with some authors considering them the same condition [Superti-Furga & Gimelli 1987].

Males with FMD1 present with the following:

  • A skeletal dysplasia manifest clinically as:
    • Distal phalangeal hypoplasia
    • Progressive contractures of the hand over the first two decades resulting in marked limitation of movement at the interphalangeal and metacarpophalangeal joints
    • Joint limitation at the wrists, elbows, knees, and ankles
    • Scoliosis that may be progressive [Morava et al 2003]
    • Limb bowing
  • Characteristic craniofacial features with very pronounced supraorbital hyperostosis, widely spaced eyes, and downslanted palpebral fissures [Gorlin & Cohen 1969]. Craniosynostosis, an occasional finding, can evolve postnatally.
  • Oligohypodontia (frequent)
  • Conductive and sensorineural hearing loss in almost all affected individuals
  • Underdevelopment of the musculature, most notably around the shoulder girdle and in the intrinsic muscles of the hands (common)
  • Extraskeletal anomalies including subglottic stenosis (which can present as congenital stridor [Leggett 1988, Mehta & Schou 1988]), urethral stenosis, and hydronephrosis
  • Cleft palate (rare)
  • Normal intelligence

Females with FMD1 present with characteristic craniofacial features similar to those of affected males [Gorlin & Winter 1980]. The digital, subglottic, and urologic anomalies observed in males with FMD1 either do not occur in females or are observed in markedly attenuated form.

Melnick-Needles Syndrome

Substantial variability is observed in females. 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.

The phenotype of four males with a pathogenic variant known to lead to conventional MNS in females has been reported. These individuals have previously described skeletal (flexed upper limbs, hypoplastic thumbs, post-axial polydactyly, bowed lower limbs, clubfeet, kyphoscoliosis and hypoplastic halluces), craniofacial (large fontanelles, 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 and unusual ophthalmologic signs (exophthalmia, widely spaced eyes, sclerocornea, cataracts, retinal angiomatosis, and a cleavage defect of the anterior chambers of both eyes) [Santos et al 2010, Naudion et al 2016, Spencer et al 2018].

Males with MNS usually present with a phenotype that is indistinguishable from, or more severe than, that associated with OPD2. Several women with classic MNS have had affected male pregnancies diagnosed in utero with a lethal phenotype reminiscent of a severe form of OPD2 [Santos et al 2010, Naudion et al 2016, Spencer et al 2018].

Females with MNS present with the following:

  • A skeletal dysplasia characterized by:
    • Short stature
    • Thoracic hypoplasia
    • Limb bowing
    • Joint subluxation
    • Scoliosis
    • Digits of both the hands and the feet that are typically long with mild distal phalangeal hypoplasia
  • Characteristic craniofacial features (prominent lateral margins of the supraorbital ridges, proptosis, full cheeks, micrognathia, facial asymmetry) [Foley et al 2010]
  • Oligohypodontia (frequent)
  • Sensorineural and conductive deafness (common)
  • Hydronephrosis secondary to ureteric obstruction (common)
  • Bleeding diathesis [Moutton et al 2016]
  • Normal intelligence
  • Normal pubertal development

Terminal Osseous Dysplasia with Pigmentary Defects

The natural history for females with terminal osseous dysplasia with pigmentary skin defects (TODPD) has been documented in one large family [Brunetti-Pierri et al 2010]. A male presentation of TODPD has never been described.

Females exhibit pronounced abnormalities of the face, hands, and skin:

  • The major skeletal findings are in the hands. There is variable shortening, fusion, and disorganized ossification of the carpals and metacarpals. Camptodactyly can be marked and forms no clear pattern. Additional features include cystic lesions and bowing of the long bones, radial head dislocation, short stature, and scoliosis.
  • Digital fibromata appear in infancy, can grow to a large size, and may re-grow after excision – but eventually involute before age ten years.
  • Cardiac septal defects
  • Ureteric obstruction (occasional)
  • Alopecia is a variable clinical finding.
  • The most characteristic craniofacial findings are widely spaced eyes, oral frenulae, and punched out hyperpigmented lesions characteristically over the temporal region. Unlike the fibromata they do not involute with age.
  • Normal intelligence
  • A male presentation of TODPD has never been described and an excess of early miscarriage in affected females has been recorded but not statistically verified.

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
  • 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.

Differential Diagnosis

Table 6.

Other Genes of Interest in the Differential Diagnosis of Otopalatodigital Spectrum Disorders

GeneDisorderMOIClinical Features of the Differential Diagnosis Disorder
Overlapping w/X-OPD-SDDifferentiating from X-OPD-SD
AMER1Osteopathia striata congenita (OMIM 300373)XLIn males: similar skeletal dysplasia to that in OPD2; occasionally, extraskeletal anomalies similar to those in OPD2In females: striations of the long bones, macrocephaly, & deafness; in males: similar skeletal phenotype to OPD2 in males
FLNBLarsen syndrome (LS) & atelosteogenesis type III (AOIII) (see FLNB-Related Disorders)ADSimilar facial features to those in OPD1 & FMD1, cleft palate, hearing loss, spatulate fingers & toesLarge joint dislocations (in both LS & AOIII) & varying degrees of disordered ossification (in AOIII)
MAP3K7Frontometaphyseal dysplasia type 2ADVery similar to FMD1Very similar to FMD1, although individuals w/MAP3K7-FMD are more likely to have cleft palate, scoliosis, cervical fusions, hearing loss, & keloid
NOTCH2Serpentine fibula-polycystic kidney disease (Hajdu-Cheney syndrome) (OMIM 102500)ADBowing of long bones, especially fibulaAcro-osteolysis, osteopenia, basilar indentation of the skull base. MNS does not incl cystic kidney disease.
SH3PXD2BFrank-ter Haar syndrome (OMIM 249420)ARSkeletal dysplasia similar to but considerably milder than in MNSMacrocornea w/or w/o glaucoma in Frank-ter Haar syndrome
SKIShprintzen-Goldberg syndrome (SGS)ADSkeletal dysplasia similar to MNS & FMD1 (e.g., tall, square-shaped vertebrae; bowed tibiae; occasionally, fusion of upper cervical vertebrae)ID & craniosynostosis in SGS
TAB2Frontometaphyseal dysplasia type 3ADVery similar to FMD1Very similar to FMD1, although individuals w/TAB2-FMD are more likely to have cleft palate, scoliosis, cervical fusions, hearing loss, & keloid

AD = autosomal dominant; AR = autosomal recessive; FMD = frontometaphyseal dysplasia; FMD1 = frontometaphyseal dysplasia type 1; ID = intellectual disability; MNS = Melnick-Needles syndrome; MOI = mode of inheritance; X-OPD-SD = X-linked otopalatodigital spectrum disorders; XL = X-linked

Possible autosomal recessive form of otopalatodigital syndrome type I. A single report of a possible autosomal recessive phenocopy of otopalatodigital syndrome type I has been described but has not been subject to molecular analysis [Zaytoun et al 2002]. The appearance of the facies and hands make this condition clinically quite distinct from the filaminopathies described here.

Management

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.

Table 7.

Recommended Evaluations Following Initial Diagnosis in Individuals with X-Linked Otopalatodigital Spectrum Disorders

System/ConcernEvaluationComment
Musculoskeletal
  • Clinical examination of extremities, joints, & spine
  • Complete skeletal survey w/scoliosis series if indicated
To evaluate for contractures, joint subluxations, scoliosis
CraniofacialClinical examination for facial or skull growth asymmetryTo evaluate for craniosynostosis
Audiology evaluationTo evaluate for conduction & sensorineural hearing loss
Clinical examination of palate & referral to ENT as necessaryTo evaluate for cleft palate & subglottic stenosis
RespiratoryReferral to pulmonologist if indicatedTo evaluate for respiratory complications assoc w/thoracic hypoplasia
CardiacEchocardiogramTo evaluate for septal defects & right ventricular outflow tract obstructive lesions
DentalDental evaluationTo evaluate for hypodontia, oligodontia
GenitourinaryRenal tract ultrasound examinationTo evaluate for ureteric & urethral obstruction & hydronephrosis
OphthalmologyClinical assessment for proptosisMonitoring for proptosis
OtherConsultation w/clinical geneticist &/or genetic counselor

Treatment of Manifestations

Table 8.

Treatment of Manifestations in Individuals with X-Linked Otopalatodigital Spectrum Disorders

Manifestation/ConcernTreatmentConsiderations/Other
Hand & foot
malformations
Surgical treatment may be required.
ScoliosisMonitoring & surgical intervention as requiredSurgery for scoliosis has had satisfactory results in several individuals.
ContracturesPhysiotherapy
Limb bowingSurgical correction of limb bowing has not been reported.
Fronto-orbital
deformity
Cosmetic surgerySurgery attempted in some individuals; regrowth following surgery does not appear to occur [Kung & Sloan 1998].
Thoracic hypoplasiaChest expansion surgeryHas been attempted in several individuals w/MNS w/marginal clinical benefit
Apnea Micrognathia & tracheobronchomalacia in severely affected individuals can → airway collapse & sleep apnea that have been successfully corrected in the most severe instances of MNS.
DeafnessHearing aidsAttempts to separate fused & misshapen ossicles are usually unsuccessful & can → formation of a perilymphatic gusher.
Laryngeal stenosisEvaluation w/anesthesiology if intubation & ventilation are required due to laryngeal stenosisLaryngeal stenosis rarely requires surgical intervention & is non-progressive w/growth.

CPAP = continuous positive airway pressure; MNS = Melnick-Needles syndrome

Surveillance

Table 9.

Recommended Surveillance for Individuals with X-Linked Otopalatodigital Spectrum Disorders

System/ConcernEvaluationFrequency
Orthopedic
manifestations
Clinical evaluation for development of:
  • Hand contractures in FMD1
  • Scoliosis in FMD1 & MNS
Annually
CraniosynostosisHead size & shape should be monitored.W/each clinical evaluation during infancy
ApneaHistory &somnography studies as indicatedYearly
DeafnessAudiology evaluations; sensorineural component can be progressive.Yearly

FMD1 = Frontometaphyseal dysplasia type 1; MNS = Melnick-Needles syndrome

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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

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:

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

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 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 Diagnosis

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 diagnosis 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 decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Alexander Graham Bell Association for the Deaf and Hard of Hearing
    3417 Volta Place Northwest
    Washington DC 20007
    Phone: 866-337-5220 (toll-free); 202-337-5220; 202-337-5221 (TTY)
    Fax: 202-337-8314
    Email: info@agbell.org
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    Suite 2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free)
    Email: contactCCA@ccakids.com
  • Face Equality International
    United Kingdom
    Email: info@faceequalityinternational.org
  • FACES: The National Craniofacial Association
    PO Box 11082
    Chattanooga TN 37401
    Phone: 800-332-2373 (toll-free)
    Email: faces@faces-cranio.org
  • Human Growth Foundation (HGF)
    997 Glen Cove Avenue
    Suite 5
    Glen Head NY 11545
    Phone: 800-451-6434 (toll-free)
    Fax: 516-671-4055
    Email: hgf1@hgfound.org
  • MAGIC Foundation
    4200 Cantera Drive #106
    Warrenville IL 60555
    Phone: 800-362-4423 (Toll-free Parent Help Line); 630-836-8200
    Fax: 630-836-8181
    Email: contactus@magicfoundation.org
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
    Email: nad.info@nad.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

X-Linked Otopalatodigital Spectrum Disorders: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
FLNAXq28Filamin-AFLNA @ LOVDFLNAFLNA

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for X-Linked Otopalatodigital Spectrum Disorders (View All in OMIM)

300017FILAMIN A; FLNA
304120OTOPALATODIGITAL SYNDROME, TYPE II; OPD2
305620FRONTOMETAPHYSEAL DYSPLASIA 1; FMD1
309350MELNICK-NEEDLES SYNDROME; MNS
311300OTOPALATODIGITAL SYNDROME, TYPE I; OPD1

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].

Table 10.

Notable FLNA Pathogenic Variants

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment
NM_001110556​.1
NP_001104026​.1
c.3552C>Ap.Asp1184GluMelnick-Needles syndrome
c.3562G>Ap.Ala1188Thr
c.3596C>Tp.Ser1199Leu
c.5217G>A 1p.Val1724_Thr1739delTerminal osseous dysplasia w/pigmentary skin defects

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

This variant occurs at the last base of an exon and is predicted to cause no amino acid change but does affect splicing resulting in deletion of 16 amino acids [Sun et al 2010].

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Chapter Notes

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
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Bookshelf ID: NBK1393PMID: 20301567

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