Bookshelf » GeneReviews » Otopalatodigital Spectrum Disorders
 
gene
GeneReviews
PagonRoberta A
BirdThomas C
DolanCynthia R
SmithRichard JH
StephensKaren
University of Washington, Seattle2009
geneticspublic health

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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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.

Otopalatodigital Spectrum Disorders
[Includes: Otopalatodigital Syndrome Type I, Otopalatodigital Syndrome Type II, Frontometaphyseal Dysplasia, Melnick-Needles Syndrome]

Stephen Robertson, FRACP, DPhil
Department of Paediatrics and Child Health
Dunedin School of Medicine
University of Otago
Dunedin, New Zealand
25072008opd
Initial Posting: November 30, 2005.
Last Revision: April 28, 2009.

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Summary

Disease characteristics. The otopalatodigital (OPD) spectrum disorders, characterized primarily by skeletal dysplasia, include: otopalatodigital syndrome type I (OPD1), otopalatodigital syndrome type II (OPD2), frontometaphyseal dysplasia (FMD), and Melnick-Needles syndrome (MNS). In males, severity ranges from mild manifestations in OPD1 to more severe presentations in FMD and OPD2; prenatal lethality is most common in males with MNS. Females exhibit variable expressivity. In OPD1, most manifestations are present at birth; and females can present with severity similar to affected males, but some have only mild manifestations. In OPD2 and FMD, 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 FMD, males do not experience progression of skeletal dysplasia but may have joint contractures and hand and foot malformations. Progressive scoliosis is observed in both 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.

Diagnosis/testing. The diagnosis is made by a combination of clinical examination, radiologic studies, family history consistent with X-linked inheritance, and molecular genetic testing. FLNA is the only gene currently known to be associated with the otopalatodigital spectrum disorders. Molecular genetic testing (sequence analysis) of the FLNA gene detects mutations in exons 3-5 in 43% of individuals with OPD1; mutations in exons 3-5 and 28-29 in 69% of individuals with OPD2; mutations in exons 3-5, 22, 28-29, and 44-47 in 57% of individuals with FMD; and mutations in exon 22 in 100% of individuals with MNS.

Management. Treatment of manifestations: hearing aids for deafness. Cosmetic surgery may correct the fronto-orbital deformity; orthopedic surgery may correct scoliosis. Surveillance: Monitor for hearing loss and orthopedic complications including scoliosis. Testing of relatives at risk: Consider molecular genetic testing for the family-specific mutation in at-risk relatives.

Genetic counseling. The OPD spectrum disorders are inherited in an X-linked manner. If a parent of a proband with OPD1, OPD2, or FMD has the FLNA mutation, the chance of transmitting the mutation in each pregnancy is 50%. When the mother has an FLNA mutation, males who inherit the mutation will be affected; females who inherit the mutation have a range of phenotypic expression. Males with OPD2 do not reproduce; males with OPD1 or FMD transmit the disease-causing mutation to all of their daughters and none of their sons. If the mother of a proband with MNS has the FLNA mutation, the chance of transmitting the mutation in each pregnancy is 50%. Males who inherit the mutation will be affected and usually die prenatally or perinatally; females who inherit the mutation have a range of phenotypic expression. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the disease-causing mutation in the family is known.

Diagnosis

Clinical Diagnosis

The otopalatodigital (OPD) spectrum disorders, a heterogeneous group of disorders characterized primarily by a skeletal dysplasia of variable severity, include the following [Verloes et al 2000]:

  • Otopalatodigital syndrome type I (OPD1)

  • Otopalatodigital syndrome type II (OPD2)

  • Frontometaphyseal dysplasia (FMD)

  • Melnick-Needles syndrome (MNS)

The diagnosis of the OPD syndromes is made by a combination of clinical examination, radiologic studies, family history consistent with X-linked inheritance, and molecular genetic testing. Clinical findings are summarized in Tables 1 and 2. Radiologic findings are presented in Table 3.

Clinical Findings

Table 1. Otopalatodigital Spectrum Disorders: Clinical/Skeletal Findings

PhenotypeShort StatureCraniofaciesThoraxSpineDigitsOther
OPD1 Characteristic 1NormalNormalShort proximally placed thumbs; hypoplastic distal phalanges; toe abnormalities 2Limited elbow extension; wrist abduction; bowed long bones
OPD2+Characteristic; more severe than OPD IHypoplasiaOccasional scoliosisHypoplastic thumbs and great toes; absent halluces, camptodactylyBowed long bones; delayed closure of the fontanels
Fronto- metaphyseal dysplasia More severe than OPD II ScoliosisDistal phalangeal hypoplasia; progressive contractures of the handsLimited range of motion (wrists, elbows, knees, ankles)
Melnick- Needles syndrome+Exorbitism, full cheeks, micrognathia, facial asymmetryHypoplasiaScoliosisLong digits, mild distal phalangeal hypoplasiaBowing; joint subluxation

1. Prominent supraorbital ridges, downslanting palpebral fissures, ocular hypertelorism, broad nasal bridge and nasal tip, hypodontia, oligodontia

2. Hypoplasia of the great toe, a long second toe, and a prominent sandal gap

Table 2. Otopalatodigital Spectrum Disorders: Other Clinical Findings

PhenotypeDeafnessCleft PalateHeartOmphaloceleGenitourinaryCNSIQ
OPD1Mixed+ Normal
OPD2Mixed+Septal defects; right ventricular outflow obstruction+Hydronephrosis; hypospadiasAbnormal 1Can be reduced
Frontometaphyseal dysplasiaMixed Urethral and ureteric obstruction Normal
Melnick-Needles syndromeMixed Hydronephrosis Normal

1. Hydrocephalus, cerebellar hypoplasia, and rarely, encephalocele and meningomyelocele

Otopalatodigital Syndrome Type I

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

  • Characteristic facial features (prominent supraorbital ridges, downslanting palpebral fissures, hypertelorism, broad nasal bridge and nasal tip)

  • Deafness (secondary either to ossicular malformation, neurosensory deficit, or a combination of both)

  • Cleft palate

  • Oligohypodontia

  • Normal intelligence

Females with OPD1 exhibit variable expressivity. Some females can be affected to a similar degree as affected, related males.

Note: One cannot confidently differentiate OPD1 from OPD2 in simplex female carriers (i.e., occurrence of a single affected female in a family with no affected males).

Otopalatodigital Syndrome Type II

Males with OPD2 [Fitch et al 1976, André et al 1981, Fitch et al 1983] present with the following:

  • A skeletal dysplasia manifest clinically as:

    • Thoracic hypoplasia

    • Limb bowing

    • Digital anomalies (most commonly hypoplasia of the first digit of the hands and feet, camptodactyly)

    • Delayed closure of the fontanels

  • Characteristic craniofacial features similar to but more pronounced than those in OPD1. Pierre Robin sequence is commonly observed.

  • 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 and a broad nasal root and 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 simplex female carriers (i.e., occurrence of a single affected female in a family with no affected males).

Frontometaphyseal Dysplasia

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

Males with FMD 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 [Morava et al 2003]

    • Limb bowing

  • Characteristic craniofacial features with very pronounced supraorbital hyperostosis, hypertelorism, and downslanting palpebral fissures [Gorlin & Cohen 1969]

  • 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 [Kanemura et al 1979, Leggett 1988, Mehta & Schou 1988]) and hydronephrosis

  • Cleft palate (rare)

  • Normal intelligence

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

Melnick-Needles Syndrome

Males with Melnick-Needles syndrome (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. Some mildly affected males have been born to clinically unaffected parents.

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, exorbitism, micrognathia) [Melnick & Needles 1966, Dereymaeker et al 1986]

  • Oligohypodontia (frequent)

  • Sensorineural and conductive deafness (common)

  • Hydronephrosis secondary to ureteric obstruction (common)

  • Normal intelligence

  • Normal pubertal development

Radiologic Findings

Table 3. Otopalatodigital Spectrum Disorders: Radiologic Findings

PhenotypeSkullSpineThoraxLong BonesHands/FeetPelvis
OPD1Sclerosis of skull base; thickening of calvarium; underdeveloped frontal sinuses; mastoids under-pneumatizedFailure of fusion of posterior vertebral arches (especially cervical) Mild bowing; dislocation of radial heads 1Contracted; lack of ilial flaring
OPD2Same as OPD1; large fontanelSame as OPD1 plus segmentation anomaliesHypoplastic; thin ribsBowed; splayed metaphyses; absent fibulae 2Same as OPD1
Frontometaphyseal dysplasiaSame as OPD1; occasionally craniosynostosisFusion of C2-3-4; deficiency of posterior vertebral archesNormal; ribs can be abnormal (coat-hanger shape)Mild bowing; undertubulation of the long bones 3
Melnick-Needles syndrome (female phenotype)Same as OPD1Increased vertebral body height, especially lumbarRibs irregular; clavicle "wavy," expansion of proximal endBowed; cortical irregularity 4Supra-acetabular constriction; ilial flaring

1. Thumb: short, broad metacarpal and distal phalangeal hypoplasia; accessory proximal ossification center of the second metacarpal; accessory carpal bones and fusion of carpal and tarsal bones

2. Abnormal modeling of the metacarpals and phalanges, more prominently on the radial side; hypoplastic or absent great toe; broad and poorly modeled phalanges and metatarsals; occasional duplication of the terminal phalanges, polydactyly

3. Carpal and tarsal fusions; erosion of the carpal bones in adolescence and adulthood; elongation and poor modeling of the metacarpals, metatarsals, and phalanges; hypoplasia of the distal phalanges of the thumb and great toes

4. Elongation and undermodeling of the phalanges, metacarpals, and metatarsals

Otopalatodigital Syndrome Type I

Males

  • Skull. Males with OPD1 have sclerosis of the skull base, thickening of the calvaria, and underdevelopment of the frontal sinuses [Taybi 1962, Dudding et al 1967]. The mastoids are typically under-pneumatized, and the mandibular angle is increased.

  • Spine. The posterior vertebral or neural arches can fail to fuse, particularly in the cervical spine.

  • Long bones. The long bones of the upper and lower limbs can be mildly bowed. Dislocation of the radial heads is common.

  • Hands and feet. An accessory proximal ossification center of the second metacarpal is characteristic. Short, broad first metacarpal and distal phalangeal hypoplasia most marked in the thumb is also characteristic. Accessory carpal bones and fusion of carpal and tarsal bones can also be observed.

  • Pelvis. The pelvis is typically contracted with a lack of normal flaring of the ilia.

Otopalatodigital Syndrome Type II

Males

  • Skull. Findings are similar to those in OPD1; but the calvarium can be greatly delayed in its ossification pattern, manifesting as large fontanels in infancy.

  • Spine. The cervical spine can, in addition to failure of fusion of the posterior neural or vertebral arches, have segmentation anomalies.

  • Long bones. The long bones of the upper and lower limbs can be bowed, with splaying of the metaphyses.

  • Hands and feet. The hands feature abnormal modeling of the metacarpals and phalanges, more prominently on the radial side. The great toe is often hypoplastic or absent entirely. The phalanges and metatarsals are characteristically broad and poorly modeled.

  • Pelvis. The pelvis is hypoplastic, with lack of normal flaring of the ilia.

Females characteristically exhibit sclerosis of the skull base and odontoid process [Robertson et al 1997]. The metaphyses of the long bones can be flared. Digital anomalies are either absent or very mild (hypoplasia of the first metacarpal or metatarsal).

Frontometaphyseal Dysplasia

Males

  • Skull. Sclerosis of the skull base, under-pneumatization of the mastoids, hypoplasia or aplasia of the paranasal sinuses, and a spur arising from the anteroinferior tip of the mandible are frequent observations. The calvarium can be markedly thickened. Craniosynostosis can occur.

  • Spine. Fusion of vertebral bodies (especially C2-3-4) and deficiency of the posterior vertebral arches are common.

  • Thorax. The thoracic cage is not hypoplastic, but the ribs can adopt a distorted shape (coat-hanger configuration).

  • Long bones. The long bones are undermodeled and frequently mildly bowed.

  • Hands and feet. Carpal and tarsal fusions are common. Erosion of the carpal bones has been observed in adolescence and adulthood. The metacarpals, metatarsals, and phalanges are elongated and poorly modeled. The distal phalanges of the thumb and great toes are hypoplastic.

Females exhibit the same cranial and long bone features as males, but to a milder degree.

Melnick-Needles Syndrome

Females

  • Skull. Skull base sclerosis and delayed closure of the fontanels is characteristic.

  • Spine. The vertebral bodies can be increased in height, especially in the lumbar region. Scoliosis is common.

  • Thorax. The ribs are irregular in contour and form. The clavicle is similarly wavy and irregular, with some expansion of its proximal end.

  • Long bones. The long bones of both limbs are bowed, with marked cortical irregularity.

  • Hands and feet. The phalanges, metacarpals, and metatarsals are all elongated and undermodeled.

  • Pelvis. The pelvis exhibits a supra-acetabular constriction with flaring of the ilia.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Gene. FLNA is the only gene currently known to be associated with the otopalatodigital (OPD) spectrum disorders.

Clinical testing

  • Sequence analysis of entire coding region and of select exons:

    • OPD1. Sequencing of FLNA exons 3-5

    • OPD2. Sequencing of FLNA exons 3-5. If the proband is female, additional exons to consider include exons 11 and 28-29.

    • FMD. FLNA mutations are widespread throughout the gene in individuals with this diagnosis. Initial screening (by either direct sequencing or DHPLC) of select exons may include exons 3-5, 22, 28-29, and 44-47.

    • MNS. Twelve females with this diagnosis have one of the three mutations found within exon 22: p.Asp1184Glu (n=1), p.Ala1188Thr (n=5), and p.Ser1199Leu (n=6) (Genotype-Phenotype Correlations). A logical strategy for molecular analysis of an individual with this condition is to sequence exon 22.

  • Deletion/duplication analysis. No deletions or duplications involving FLNA as causative of otopalatodigital syndrome have been reported. However, with newly available deletion/duplication testing methods, it may be appropriate in some instances to test symptomatic individuals who had a negative test result by sequence analysis of the entire coding region.

Research testing. Mutation scanning of the entire FLNA gene

Table 4 summarizes molecular genetic testing for this disorder.

Table 4. Molecular Genetic Testing Used in Otopalatodigital Spectrum Disorders

Gene SymbolTest MethodPhenotypeMutations DetectedMutation Detection Frequency 1Test Availability
FLNASequence analysis of entire gene or select exonsOPD1Missense mutations in exons 3-543% (n=7)Clinical graphic element
OPD2Missense mutations69% (n=13)
FMDSequence variants57% (n=23) 2
MNSMissense mutations in exon 22100% (n=12)
Deletion/duplication analysis 3Undefined4Partial- and whole-gene deletions/duplicationsUnknown

1. Analysis by mutation scanning of entire FLNA gene [Robertson et al 2006b]

3. Testing that identifies deletions/duplications not detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation dependent probe amplification (MLPA), and array CGH may be used.

4. Large deletions and duplications have been associated with allelic conditions such as myxomatous cardiac valvular dystrophy (see Genetically Related Disorders).

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Confirming the diagnosis in a proband. Clinical diagnosis may guide the order of screening of select exons of the FLNA gene.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Little is known about the natural history of the otopalatodigital (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 I (OPD1), to a more severe presentation in frontometaphyseal dysplasia (FMD) and otopalatodigital syndrome type II (OPD2). Prenatal lethality is the most common clinical phenotype in males with Melnick-Needles syndrome (MNS) [Donnenfeld et al 1987].

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 FMD, females are less severely affected than related affected males [Fitzsimmons et al 1982, Robertson et al 1997].

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

Final height can be mildly reduced, but individuals have been characterized with mutations in FLNA and stature greater than the 90th percentile. Pubertal development and intelligence is normal in affected individuals.

Carrier females may develop conductive or neurosensory hearing loss.

Otopalatodigital syndrome type II. Most affected males do not survive beyond the first year of life, usually secondary to thoracic hypoplasia with resulting pulmonary insufficiency.

Males who live beyond the first year of life are usually developmentally delayed and require assistance with feeding and respiratory support.

Frontometaphyseal dysplasia. Males do not experience progression of their skeletal dysplasia but may develop secondary complications of joint contractures. Progressive scoliosis has been described in both males and females.

Melnick-Needles syndrome. Substantial variability is observed. 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. Occasionally, males can survive the neonatal period but do not live beyond the first year of life [Robertson et al 1997, Verloes et al 2000].

Genotype-Phenotype Correlations

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

  • Otopalatodigital syndrome type I. All males with this diagnosis had mutations in exons 3, 4, or 5 (see Table 7; pdf).

  • Otopalatodigital syndrome type II. All males with this diagnosis had mutations in exons 3, 4, or 5. Females with a phenotype similar to males with typical OPD2 had mutations in exons 28 and 29 (see Table 7).

  • Frontometaphyseal dysplasia

  • Melnick-Needles syndrome. Twelve affected females had one of three mutations in exon 22 of FLN, resulting in the following amino acid changes: p.Asp1184Glu (n=1), p.Ala1188Thr (n=5), and p.Ser1199Leu (n=6) (see Table 7).

Penetrance

Penetrance in males with an FLNA mutation leading to an OPD spectrum disorder is complete.

Some obligate carrier females with FLNA mutations leading to OPD1 have a normal clinical appearance. It is unclear what proportion of such females have radiographic indicators of their carrier status.

Anticipation

No evidence suggests genetic anticipation in these disorders.

Nomenclature

The term “otopalatodigital syndrome spectrum disorders” is an umbrella category for four discrete but clinically related conditions, namely: frontometaphyseal dysplasia, Melnick-Needles syndrome (originally referred to as osteodysplasty), otopalatodigital syndrome type I (also called Taybi syndrome after its first description in 1963), and otopalatodigital syndrome type II. The term “spectrum” reflects the fact that, although most individuals can be unambiguously diagnosed with one of the constituent phenotypes, overlapping of the phenotypes has been observed.

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

Prevalence

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

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

Frank-ter Haar syndrome is an autosomal recessive syndrome with a skeletal dysplasia that is similar to but considerably milder than that seen in Melnick-Needles syndrome (MNS). Macrocornea with or without glaucoma is a differentiating feature.

Osteopathia striata congenita features striations of the long bones and a similar skeletal dysplasia to that seen in OPD2. Occasionally, males have been reported with similar extra-skeletal anomalies to those seen in OPD2. Controversy exists as to whether some families exhibit autosomal dominant instead of X-linked inheritance.

Serpentine fibula-polycystic kidney disease has some skeletal manifestations that resemble those of MNS, but MNS does not include cystic kidney disease. Sequence analysis in one individual did not identify an FLNA mutation [Albano et al 2007].

Filamin B-related disorders. Larsen syndrome (LS) and atelosteogenesis type III (AOIII) have several phenotypic similarities to OPD1 and OPD2, respectively. This clinical similarity reflects the close homology shared by their respective causative genes, FLNB and FLNA, and a similar clustered distribution of mutations. Differentiating features are the autosomal dominant inheritance of the filamin B-related conditions, the presence of large joint dislocations (in both LS and AOIII), and varying degrees of disordered ossification (in AOIII).

Shprintzen-Goldberg syndrome (SGS). A disorder of unknown cause, Shprintzen-Goldberg syndrome is characterized by craniosynostosis, mental retardation, and a skeletal dysplasia similar to that observed in MNS and FMD. Skeletal findings in common include tall, square-shaped vertebrae, bowed tibiae, and, occasionally, fusion of upper cervical vertebrae. The presence of mental retardation and craniosynostosis usually allows this condition to be distinguished from MNS or FMD.

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].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with otopalatodigital (OPD) spectrum disorders, the following evaluations are recommended:

Treatment of Manifestations

  • Deafness is managed with hearing aids (see Deafness and Hereditary Hearing Loss Overview). 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.

  • Stridor in the neonatal period on account of laryngeal stenosis rarely requires surgical intervention and is non-progressive with growth.

  • Cosmetic surgery to correct the fronto-orbital deformity has been attempted in some individuals. Re-growth post surgery does not seem to occur [Kung & Sloan 1998]. Hand and foot malformations may also require surgery.

  • Orthopedic surgery

    • Surgical correction of limb bowing has not been reported.

    • Several individuals have had scoliosis surgically addressed, with satisfactory results.

    • Chest expansion surgery has been attempted in several individuals with Melnick-Needles syndrome, with only marginal clinical benefit.

  • Apnea prevention. Micrognathia and tracheobronchomalacia in severely affected individuals can lead to airway collapse and sleep apnea that have been successfully corrected with continuous positive airway pressure (CPAP) [Lan et al 2006].

Prevention of Secondary Complications

Anesthetists should be aware of the associated laryngeal stenosis, if intubation and ventilation are required [Leggett 1988, Mehta & Schou 1988].

Surveillance

Clinical evaluation for development of orthopedic manifestations (e.g., hand contractures in FMD, scoliosis in FMD and MNS) is appropriate.

Monitoring of hearing loss should be ongoing, as the sensorineural component can be progressive.

Testing of Relatives at Risk

Consider molecular genetic testing for the family-specific mutation in all at-risk relatives

Because affected individuals may benefit from early evaluations for hearing loss and orthopedic complications, including scoliosis, molecular genetic testing for the family-specific mutation in all at-risk relatives should be considered.

If molecular genetic testing is not an option for an at-risk child, evaluations for hearing loss and orthopedic complications, including scoliosis, should be instituted as soon as possible after a clinical diagnosis is established in the at-risk relative.

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

Therapies Under Investigation

Search ClinicalTrials.gov 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.

Other

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.

Mode of Inheritance

The otopalatodigital spectrum disorders (OPD spectrum disorders) are inherited in an X-linked manner.

Risk to Family Members — OPD1, OPD2, or Frontometaphyseal Dysplasia (FMD)

Parents of a male proband with OPD1, OPD2, or FMD

Parents of a female proband with OPD1, OPD2, or FMD

Sibs of a male proband with OPD1, OPD2, or FMD

  • The risk to the sibs of a proband depends on the genetic status of the parents.

  • If a parent has an FLNA mutation, the chance of transmitting the mutation in each pregnancy is 50%:

    • When the mother has an FLNA mutation, male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will have a range of possible phenotypic expression.

    • When the father has an FLNA mutation, all female sibs will inherit the mutation; male sibs will not inherit the mutation.

  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low but greater than that of the general population:

Offspring of a male proband with OPD1, OPD2, or FMD. Males with OPD2 do not reproduce. Males with OPD1 or FMD transmit the disease-causing mutation to all of their daughters and none of their sons.

Offspring of a female proband with OPD1, OPD2, or FMD. Women with an FLNA gene mutation have a 50% chance of transmitting the disease-causing mutation to each child: sons who inherit the mutation will be affected; daughters will have a range of possible phenotypic expression.

Other family members of a proband with OPD1, OPD2, or FMD. If a parent of the proband is found to also have a disease-causing mutation, his or her female family members may be at risk of having the mutation and being asymptomatic or symptomatic; and his or her male family members may be at risk of being affected depending on their genetic relationship to the proband.

Risk to Family Members — Melnick-Needles Syndrome (MNS)

Parents of a male proband with MNS

Parents of a female proband with MNS. If the proband is a female and if pedigree analysis reveals that she is the only affected family member, it is reasonable to offer molecular genetic testing to her mother to determine risks to family members.

Sibs of a proband with MNS

  • The risk to the sibs of a proband depends on the genetic status of the mother.

  • If the mother has the gene mutation, the chance of transmitting the FLNA mutation in each pregnancy is 50%:

    • Male sibs who inherit the mutation will be affected and generally die prenatally or perinatally; female sibs who inherit the mutation will have a range of possible phenotypic expression.

  • When the mother is clinically unaffected, the risk to the sibs of a proband appears to be low but greater than that of the general population:

Offspring of a male proband with MNS. Males with MNS usually die in the pre- or perinatal period and do not reproduce.

Offspring of a female proband with MNS. Women with an FLNA gene mutation have a 50% chance of transmitting the disease-causing mutation to each child; sons who inherit the mutation will be affected and generally die prenatally; daughters will have a range of possible phenotypic expression.

Carrier Detection

Carrier testing for at-risk family members is available on a clinical basis once the FLNA mutation has been identified in the family.

Related Genetic Counseling Issues

See Management for information on testing 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. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See graphic element for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

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

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 [Eccles et al 1994].

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see graphic element.

Molecular Genetics

Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.

Table A. Molecular Genetics of Otopalatodigital Spectrum Disorders

Gene SymbolChromosomal LocusProtein Name
FLNAXq28Filamin-A

Data are compiled from the following standard references: gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.

Table B. OMIM Entries for Otopalatodigital Spectrum Disorders

300017 FILAMIN A; FLNA
300049 HETEROTOPIA, PERIVENTRICULAR, X-LINKED DOMINANT
304120 OTOPALATODIGITAL SYNDROME, TYPE II; OPD2
305620 FRONTOMETAPHYSEAL DYSPLASIA; FMD
309350 MELNICK-NEEDLES SYNDROME; MNS
311300 OTOPALATODIGITAL SYNDROME, TYPE I; OPD1

Table C. Genomic Databases for Otopalatodigital Spectrum Disorders

Gene SymbolEntrez GeneHGMD
FLNA2316 (MIM No. 300049)FLNA

For a description of the genomic databases listed, click here.

Note: HGMD requires registration.

Molecular Genetic Pathogenesis

The filamin class of actin-binding proteins is known to regulate cell stability, protrusion, and motility across various biologic systems [Gorlin et al 1990, Cunningham et al 1992, Ott et al 1998, Leonardi et al 2000, Stahlhut & van Deurs 2000]. Filamin-deficient melanocytes fail to undergo locomotion in response to factors that elicit migration in the same filamin-expressing cells. They exhibit prolonged circumferential blebbing, abnormal phagocytosis, and impaired volume regulation, perhaps secondary to abnormal regulation of sodium channel activity. A similar defect is observed in filamin-deficient macrophages with disruption of myosin during spreading and phagocytosis [Stendahl et al 1980]. Filamin is also required for cell motility and pseudopod formation in the slime mold, Dictyostelium discoideum, suggesting a highly conserved function across species [Cox et al 1996]. A direct mechanism can be drawn with the association of filamin and integrins, which have been implicated in cell adhesion and migration.

The contrast in phenotypic consequences among loss-of-function mutations (leading to periventricular nodular heterotopia) and clustered missense mutations (leading to the OPD spectrum disorders) suggests that different mechanisms are contributing to the pathogenesis of these conditions. Filamins coordinate and integrate cell signaling and subsequent remodeling of the actin cytoskeleton. The complexity of these integrative functions makes the implication of individual functions in the pathogenesis of these conditions difficult. However, 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]. Filamin A may have a similar influence on neuroblast migration during cortical development within the central nervous system. Disruption of this process likely results in the formation of periventricular heterotopias. 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 OPD spectrum disorder phenotypes.

Normal allelic variants. As with other loci within Xq28, the level of polymorphism in the FLNA gene is low. Several synonymous and non-synonymous variants have been shown to be present in healthy individuals (see Table 5; pdf), including some that have been reported in the literature (incorrectly) as causal of disease phenotypes [Masruha et al 2006]. The gene encoding filamin A, FLNA, encompasses 48 exons spread over 26 kb on chromosome Xq28. The FLNA transcript is 8.3 kb (see Table 5; pdf).

Pathologic allelic variants. Mutations that lead to the otopalatodigital spectrum disorders are substitutions or small deletions of amino acid residues. These alterations occur in defined regions of the filamin A protein (see Abnormal gene product). Substitutions in the distal portion of the actin-binding domain (termed calponin homology domain 2) lead to OPD1 and OPD2. In contrast, only three mutations (two of them highly recurrent and located within exon 22) lead to Melnick-Needles syndrome. Mutations that lead to frontometaphyseal dysplasia are the most widely dispersed, being located in regions that encode the actin binding domain, repeats 3, 9/10, 14/15, and 22/23. This distribution of mutations indicates that very specific functions of filamins are being altered to lead to the OPD spectrum disorders, in contrast to a global loss of function that results in the periventricular nodular heterotopia phenotype.

Table 6. Selected FLNA Pathologic Allelic Variants

Phenotype 1DNA
Nucleotide Change
(Alias 2)
Protein Amino
Acid Change
Reference
Sequence
Otopalatodigital spectrum disorders (Melnick-Needles syndrome)c.3552C>Ap.Asp1184GluNM_001110556.1
NP_001104026.1
c.3562G>Ap.Ala1188Thr
c.3596C>Tp.Ser1199Leu
Periventricular nodular heterotopiac.65_66delAC (2 bp del exon 2)p.Thr23AlafsX82
c.1923C>Tp.Tyr643GlyfsX39 3
Myxomatous cardiac valvular dystrophyg.10807_12749delinsTG (1.9kb deletion)p.Val761_Gln942delNT_011726.13

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

2. Variant designation that does not conform to current naming conventions

3. Specific splicing variant described in Hehr et al [2006]

See Table 7 (pdf).

Normal gene product. Filamin A is a 280-kd filamentous protein comprising 2647 amino acids. The protein links membrane receptors to the actin cytoskeleton and represents a crucial link between signal transduction and the cytoskeleton. The protein consists of an actin-binding domain at the amino terminus, 23 repeats that resemble Ig-like domains and which form a chain-like structure interrupted by two hinge regions, and a C-terminal repeat that undergoes dimerization. There are two principal isoforms of the protein, produced from alternative splicing of exon 32 that encodes a “hinge” domain. Two other filamins, filamin B and filamin C, are encoded by autosomal loci and share significant similarity at the protein level.

Abnormal gene product. Mutations that lead to the otopalatodigital spectrum disorders are predicted to result in filamin A proteins with substitutions or small deletions of amino acid residues. These alterations occur in defined regions of the filamin A protein (see Pathologic allelic variants). This distribution of mutations indicates that very specific functions of filamins are being altered to lead to the OPD spectrum disorders, in contrast to a global loss of function that results in the periventricular nodular heterotopia phenotype. This pattern of clustered missense mutations suggests that key interactions with filamin or localized domains of filamin that have regulatory functions are altered by these mutations. No specific functions of filamin have been unequivocally linked to the pathogenesis of the OPD spectrum disorders to date.

Resources

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select graphic element for the most up-to-date Resources information.—ED.

AboutFace International
123 Edward Street, Suite 1003
Toronto, Ontario
M5G 1E2 Canada
Phone: 800-665-FACE (800-665-3223); 416-597-2229
Fax: 416-597-8494
Email:
www.aboutfaceinternational.org

Alexander Graham Bell Association for the Deaf and Hard of Hearing
3417 Volta Place Northwest
Washington, DC 20007
Phone: 866-337-5220; 202-337-5220; 202-337-5221 (TTY)
Fax: 202-337-8314
Email:
www.agbell.org

American Society for Deaf Children
3820 Hartzdale Drive
Camp Hill PA 17011
Phone: 800-942-2732 (parent hotline); 717-703-0073 (business V/TTY)
Fax: 717-909-5599
Email:
www.deafchildren.org

Children's Craniofacial Association
13140 Coit Road, Suite 307
Dallas, TX 75240
Phone: 800-535-3643; 214-570- 9099
Fax: 214-570-8811
Email:
www.ccakids.com

FACES: The National Craniofacial Association
PO Box 11082
Chattanooga, TN 37401
Phone: 800-332-2373; 423-266-1632
Email:
www.faces-cranio.org

Human Growth Foundation
997 Glen Cove Avenue, Suite 5
Glen Head, NY 11545
Phone: 800-451-6434
Fax: 516-671-4055
Email:
www.hgfound.org

The MAGIC Foundation
6645 West North Avenue
Oak Park, IL 60302
Phone: 800-362-4423; 708-383-0808
Fax: 708-383-0899
Email: info@magicfoundation.org
www.magicfoundation.org

National Association of the Deaf
8630 Fenton Street Suite 820
Silver Spring, MD 20910
Phone: 301-587-1788 (voice); 301-587-1789 (TTY)
Fax: 301-587-1791
Email:
www.nad.org

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page. graphic element

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Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Suggested Reading

Feng Y, Chen MH, Moskowitz IP, Mendonza AM, Vidali L, Nakamura F, Kwiatkowski DJ, Walsh CA. Filamin A (FLNA) is required for cell-cell contact in vascular development and cardiac morphogenesis. Proc Natl Acad Sci USA. 2006; 103: 1983641. [PubMed]

Chapter Notes

Acknowledgments

The author is supported by the Child Health Research Foundation of New Zealand.

Revision History

  • 28 April 2009 (cd) Revision: Deletion/duplication analysis available clinically

  • 25 July 2008 (me) Comprehensive update posted live

  • 30 November 2005 (me) Review posted to live Web site

  • 14 March 2005 (sr) Original submission

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