X-Linked Otopalatodigital Spectrum Disorders
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 testing and preimplantation genetic testing are possible if the pathogenic variant in the family is known.
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
| Phenotype | Craniofacial Features | Skeletal Features | Other |
|---|---|---|---|
| OPD1 (male phenotype) | Cleft palate & characteristic facies: prominent supraorbital ridges, downslanted palpebral fissures, hypertelorism, broad nasal bridge & nasal tip, hypodontia, oligodontia | Digits: short proximally placed thumbs, hypoplastic distal phalanges, great toe hypoplasia, long 2nd toe, prominent sandal gap; limited joint mobility; limbs w/mild bowing | Conductive & 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 stature | Conductive & 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 limbs | Conductive & 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 asymmetry | Digits: long w/mild distal phalangeal hypoplasia; thoracic hypoplasia; bowed limbs; joint subluxation; short stature | Conductive & 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, alopecia | Digits: fibromata in infancy, camptodactyly; bowed limbs; short stature | Cardiac: 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
| Phenotype | Skull | Spine | Thorax | Long Bones | Hands / Feet | Pelvis |
|---|---|---|---|---|---|---|
| OPD1 (male phenotype) | Sclerosis of skull base; thickened calvarium; underdeveloped frontal sinuses; mastoids under-pneumatized | Failure of fusion of posterior vertebral arches (especially cervical) | Mild bowing; dislocation of radial heads | Thumb w/short, broad metacarpal; distal phalangeal hypoplasia; accessory proximal ossification center of 2nd metacarpal; accessory carpal bones; fusion of carpal & tarsal bones | Contracted; no iliac flaring | |
| OPD2 (male phenotype) | Same as OPD1; large fontanelles | Same as OPD1; segmentation anomalies | Hypoplastic; thin ribs | Bowed; splayed metaphyses; absent fibulae | Broad, poorly modeled phalanges, metacarpals & metatarsals; ± duplicated terminal phalanges | Same as OPD1 |
| FMD1 (male phenotype) | Same as OPD1; occasionally, craniosynostosis | Fusion of C2-3-4; deficiency of posterior vertebral arches | ± coat-hanger shape ribs | Mild bowing; undertubulation | Carpal & 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; scoliosis | Hypoplasia; ribs irregular; wavy clavicle w/expansion of proximal end | Bowed, sometimes ribbon-like; cortical irregularity | Elongation & undermodeling of phalanges, metacarpals & metatarsals | Supra-acetabular constriction; iliac flaring |
| TODPD (female phenotype) | Normal | Scoliosis | No abnormalities consistently described | Irregular ossification; cystic lesions near epiphyses; bowed; radial head dislocation | Hypoplasia, shortening, irregular ossification &/or fusions of carpals & metacarpals; irregular cortices | Narrow 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 1 | Method | Phenotype | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|---|
| FLNA | Sequence analysis 3 | OPD1 | 94% (n=15) 4 |
| OPD2 | 100% (n=19) 4 | ||
| FMD1 | 71% (n=47) 5 | ||
| MNS | 100% (n=27) 4 | ||
| Targeted analysis for c.5217G>A | TODPD | 100% (n=6) 6 | |
| Gene-targeted deletion/duplication analysis 7 | None 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.
See Table A. Genes and Databases for chromosome locus and protein.
- 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. 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.
Robertson et al [2006b]
- 5.
Robertson et al [2006a], Wade et al [2016]
- 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
| Disorder | Features | % of Persons with Feature |
|---|---|---|
| OPD1 in males | Digital anomalies | 100% |
| Deafness | 100% | |
| Mild limb bowing | Unknown | |
| Cleft Palate | 75% | |
| OPD2 in males | Thoracic hypoplasia | 100% |
| Cleft palate | 80% | |
| FMD1 in males | Supraorbital hyperostosis | 100% |
| Urinary Tract obstruction | Unknown | |
| MNS in females | Micrognathia | 100% |
| Limb bowing | 100% | |
| Short stature | 100% | |
| Thoracic hypoplasia | 100% | |
| TODPD in females | Digital fibromata | 100% |
| Erosive changes on radiographs | 100% | |
| Limb bowing | Unknown |
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