X-Linked Otopalatodigital Spectrum Disorders

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.

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.