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Otopalatodigital Spectrum Disorders

Includes: Frontometaphyseal Dysplasia, Melnick-Needles Syndrome, Otopalatodigital Syndrome Type I, Otopalatodigital Syndrome Type II, Terminal Osseous Dysplasia with Pigmentary Skin Defects
, FRACP, DPhil
Department of Paediatrics and Child Health
Dunedin School of Medicine
University of Otago
Dunedin, New Zealand

Initial Posting: ; Last Update: May 2, 2013.

Summary

Disease characteristics. The otopalatodigital (OPD) spectrum disorders, characterized primarily by skeletal dysplasia, include the following:

  • Otopalatodigital syndrome type I (OPD1)
  • Otopalatodigital syndrome type II (OPD2)
  • Frontometaphyseal dysplasia (FMD)
  • 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 FMD, females are less severely affected than related affected males. Males do not experience progression of 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. Prenatal lethality is most common in males with MNS. TODPD is a female limited condition, characterized by terminal skeletal dysplasia, pigmentary defects of the skin, and recurrent digital fibromata.

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 in which mutations are known to cause the otopalatodigital spectrum disorders. Molecular genetic testing (sequence analysis) of FLNA detects mutations of individuals with OPD1, OPD2, FMD, MNS, and TODPD.

Management. Treatment of manifestations: Hearing aids for deafness. Cosmetic surgery may correct the fronto-orbital deformity; orthopedic surgery may correct scoliosis; continuous positive airway pressure (CPAP) and mandibular distraction can improve airway complications related to micrognathia.

Surveillance: Monitor for hearing loss and orthopedic complications including scoliosis and craniosynostosis.

Evaluation 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 TODPD or 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 exhibit embryonic lethality or die perinatally (MNS); 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]:

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 StatureCraniofaciesThoraxScoliosisDigitsOther
OPD1 Characteristic 1 NormalShort proximally placed thumbs; hypoplastic distal phalanges; toe abnormalities 2 Limited elbow extension; wrist abduction; bowed long bones
OPD2+Characteristic; more severe than OPD IHypoplasiaOccasional Hypoplastic thumbs and great toes; absent halluces, camptodactylyBowed long bones; delayed closure of the fontanels
Fronto-metaphyseal dysplasia More severe than OPD II +Distal phalangeal hypoplasia; progressive contractures of the handsLimited range of motion (wrists, elbows, knees, ankles)
Melnick-Needles syndrome+Proptosis , full cheeks, micrognathia, facial asymmetryHypoplasia+Long digits, mild distal phalangeal hypoplasiaBowing; joint subluxation
Terminal osseous dysplasia with pigmentary skin defects+Widely spaced eyes, pigmentary skin defects, oral frenulae, alopeciaNormal+Amorphous ossification, fusions, hypoplasiaCystic lesions and bowing of long bones; radial head dislocation; resolving fibromata in infancy

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
FMDMixed  Urethral and ureteric obstruction Normal
MNSMixed   Hydronephrosis Normal
TODPD--Septal defects-Occasional ureteric obstruction-Normal

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

Otopalatodigital Syndrome Type I (OPD1)

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, downslanted palpebral fissures, widely spaced eyes, widenasal bridge and broad 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 (OPD2)

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, 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 simplex female carriers (i.e., occurrence of a single affected female in a family with no affected males).

Frontometaphyseal Dysplasia (FMD)

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, widely spaced eyes, and downslanted palpebral fissures [Gorlin & Cohen 1969]. Craniosynostosis can be an occasional finding.
  • 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]), urethral stenosis 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 (MNS)

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 [Santos et al 2010]. 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, proptosis, 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

Terminal Osseous Dysplasia with Pigmentary Skin Defects (TODPD)

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.
  • Digital fibromata appear in infancy and can grow to a large size; may re-grow after excision but eventually involute before age ten years.
  • 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.
  • 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.

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 headsSee footnote 1Contracted; lack of ilial flaring
OPD2Same as OPD1; large fontanelSame as OPD1 plus segmentation anomaliesHypoplastic; thin ribsBowed; splayed metaphyses; absent fibulaeSee footnote 2Same as OPD1
FMDSame 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 bonesSee footnote 3 
MNS (female phenotype)Same as OPD1Increased vertebral body height, especially lumbarRibs irregular; clavicle "wavy," expansion of proximal endBowed; cortical irregularitySee footnote 4Supra-acetabular constriction; ilial flaring
TODPDNormalScoliosisNo abnormalities consistently describedIrregular ossification, cystic lesions particularly near epiphyses, bowingSee footnote 5Coxa vara

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

5. Hypoplasia, shortening, irregular ossification, and/or joint fusions of carpal and metacarpal bones

Otopalatodigital Syndrome Type I (OPD1)

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 (OPD2)

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 (FMD)

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 (MNS)

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.

Terminal Osseous Dysplasia with Pigmentary Defects (TODPD)

Females

  • Skull. Skull has a relatively normal appearance with not as much skull base sclerosis as has been associated with FMD and MNS.
  • Spine. Scoliosis is common.
  • Thorax. Thoracic cage is mildly hypoplastic.
  • Long bones. Long bones show marked abnormalities of ossification with cystic lucencies, bowing, and cortical irregularity.
  • Hands and feet. Findings include markedly irregular hypoplasia, irregular ossification, abnormal modeling, and fusion of metacarpal, carpal, metatarsal, and tarsal bones.

Molecular Genetic Testing

Gene. FLNA is the only gene in which mutations are known to cause the otopalatodigital (OPD) spectrum disorders.

Clinical testing

Table 4. Summary of Molecular Genetic Testing Used in Otopalatodigital Spectrum Disorders

Gene 1Test MethodPhenotypeMutations Detected 2Mutation Detection Frequency 3,4
FLNASequence analysis of entire gene 5 OPD1Missense mutations 94% (n=15)
OPD2Missense mutations100% (n=19)
FMDSequence variants 6,768% (n=47) 6
MNSMissense mutations100% (n=27)
TODPDMissense mutation c.5217G>A 8100% (n=6)
Deletion/duplication analysis 9Partial- and whole-gene deletions/duplications Unknown 10

1. See Table A. Genes and Databases for chromosome locus and protein name.

1. Some phenotypes tend to have mutations in specific exons; see Molecular Genetics.

2. The ability of the test method used to detect a mutation that is present in the indicated gene

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

4. Some laboratories may offer sequence analysis of select exons.

5. Robertson et al [2006a]

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

7. All reported cases of this condition have been shown to be 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 mutation appears to define this disorder.

8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

9. 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- / whole-gene deletions do not cause an OPD spectrum disorder phenotype.

Testing Strategy

To confirm/establish the diagnosis in a proband. Sequence analysis of FLNA should be performed.

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 OPD spectrum disorders. Whole-gene duplications (in association with neighboring genes) have been associated with intellectual disability and seizures (see Genetically Related Disorders).

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. Craniosynostosis can evolve postnatally.

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 typically live beyond the first year of life [Robertson et al 1997, Verloes et al 2000, Santos et al 2010].

The phenotype of one male with a mutation known to lead to conventional MNS in females has been reported. This individual had previously described skeletal (flexed upper limbs, hypoplastic thumbs, post-axial polydactyly, bowed lower limbs, clubfeet, kyphoscoliosis and hypoplastic halluces), craniofacial (large fontanels, 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 but unusual ophthalmological signs (exophthalmia, widely spaced eyes, sclerocornea, cataracts, retinal angiomatosis and a cleavage defect of the anterior chambers of both eyes) [Santos et al 2010].

Terminal osseous dysplasia with pigmentary defects. The natural history for females with this condition is not well documented in the literature. A male presentation of TODPD has never been described.

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.
  • 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.
  • Frontometaphyseal dysplasia
  • Melnick-Needles syndrome. The vast majority (>90%) of individuals with MNS have mutations in exon 22 of FLNA, with the two preponderant mutations being p.Ala1188Thr and p.Ser1199Leu. Rare individuals have had mutations identified in exons 6 and 23.

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. What proportion of such females have radiographic indicators of their carrier status is not clear.

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 some of 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

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. This condition is caused by mutations in SH3PXD2B.

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. Mutations in WTX cause this condition.

Serpentine fibula-polycystic kidney disease has some skeletal manifestations that resemble those of MNS, but MNS does not include cystic kidney disease [Albano et al 2007]. Mutations in NOTCH2 cause this condition.

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 associated 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) is characterized by craniosynostosis, intellectual disability, 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 intellectual disability and craniosynostosis usually allows this condition to be distinguished from MNS or FMD. SGS is caused by mutations in SKI.

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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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] and mandibular distraction in the most severe instances of MNS.

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. Head size and shape should be monitored as part of the surveillance for evolving craniosynostosis.

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

Evaluation 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.

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 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

  • The father of an affected male will not have the disease nor will he be a carrier of the mutation.
  • In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
  • If pedigree analysis reveals that the proband is the only affected family member, four possible genetic explanations exist:
    • The proband has a de novo mutation. In this instance, the proband's mother does not have a gene mutation; and the only other family members at risk are the offspring of the proband. De novo mutations are common in the otopalatodigital spectrum disorders.
    • The proband's mother has a de novo mutation. Two types of de novo mutations may be present in the mother:
      a.

      A de novo germline mutation that was present at the time of her conception, is present in every cell of her body, and is detectable in DNA extracted from her leukocytes

      OR

      b.

      A mutation that is present in some of her germ cells only (termed "germline mosaicism") and is not detectable in DNA extracted from her leukocytes. Germline mosaicism has been reported in otopalatodigital syndrome type I and therefore should be considered in the genetic counseling of at-risk family members [Robertson et al 2006b].

      In both instances (a. and b.) each of the proband’s mother’s offspring is at risk of inheriting the mutation; none of the proband’s mother’s sibs, however, is at risk of inheriting the mutation.

    • The mother is a carrier and has inherited the disease-causing mutation either from her mother, who has a disease-causing mutation, or from her asymptomatic father, who is mosaic for the mutation.

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

  • If the proband is a female with OPD1, OPD2, or FMD, and if pedigree analysis reveals that she is the only affected family member, it is reasonable to offer molecular genetic testing to both of her parents to determine risks to family members.
  • If the proband’s father is asymptomatic, it is possible that he has the mutation in some cells in his body (somatic mosaicism). If her father is asymptomatic and does not have somatic mosaicism for the altered gene, the possible genetic explanations for the origin of the proband’s gene mutation are the same as for a male proband with a negative family history.
  • Somatic mosaicism for mutations leading to the 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 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:
    • If the disease-causing mutation cannot be detected in the DNA of either parent of the proband, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband.
    • Germline mosaicism has been observed in a family with otopalatodigital syndrome type I and is therefore a possibility.

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 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) or Terminal Osseous Dysplasia with Pigmentary Skin Defects (TODPD)

Parents of a male proband with MNS

  • The father of an affected male will not have the disease nor will he be a carrier of the mutation.

  • In a family with affected individuals in more than one generation, the mother of an affected male is an obligate carrier.

  • If pedigree analysis reveals that the proband is the only affected family member, four possible genetic explanations exist:

    • The proband has a de novo mutation, in which case the proband's mother does not have a gene mutation. De novo mutations are common in the otopalatodigital spectrum disorders.
    • The proband's mother has a de novo mutation. Two types of de novo mutations may be present in the mother:
  • a.

    A germline mutation that was present at the time of her conception. It is present in every cell of her body and is detectable in DNA extracted from her leukocytes

    OR

    b.

    A mutation that is present in some of her germ cells only (termed "germline mosaicism") and is not detectable in DNA extracted from her leukocytes. Germline mosaicism has been demonstrated in the otopalatodigital spectrum disorders.

    In both instances (a. and b.) each of the proband's mother's offspring is at risk of inheriting the mutation; none of the proband's mother's sibs, however, is at risk of inheriting the mutation.

    Parents of a female proband with MNS or TODPD. 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 or TODPD

    • 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 of a proband with MNS 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.
      • Female sibs of a proband with TODPD 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 or TORPD. Women with an FLNA 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 possible if the FLNA mutation has been identified in the family.

    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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

    Prenatal Testing

    Molecular genetic testing. If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

    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 an option for some families in which the disease-causing mutation has been identified.

    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.

    • AboutFace International
      123 Edward Street
      Suite 1003
      Toronto Ontario M5G 1E2
      Canada
      Phone: 800-665-3223 (toll-free); 416-597-2229
      Fax: 416-597-8494
      Email: info@aboutfaceinternational.org
    • 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
      #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); 214-570-9099
      Fax: 214-570-8811
      Email: contactCCA@ccakids.com
    • 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
      6645 West North Avenue
      Oak Park IL 60302
      Phone: 800-362-4423 (Toll-free Parent Help Line); 708-383-0808
      Fax: 708-383-0899
      Email: info@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. Otopalatodigital Spectrum Disorders: Genes and Databases

    Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
    FLNAXq28Filamin-AFLNA @ LOVDFLNA

    Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

    Table B. OMIM Entries for Otopalatodigital Spectrum Disorders (View All in OMIM)

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

    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 between the phenotypic consequences of loss-of-function mutations (leading to periventricular nodular heterotopia) and those of the clustered missense mutations (leading to the OPD spectrum disorders) is less well understood. Some of these mutations enhance that affinity of filamin A for binding actin. 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 normal allelic variants in FLNA is low. Several synonymous and nonsynonymous variants have been shown to be present in healthy individuals including some that have been reported in the literature (incorrectly) as causal of disease phenotypes [Masruha et al 2006]. FLNA, which encodes the protein filamin A, encompasses 48 exons spread over 26 kb on chromosome Xq28. The FLNA transcript is 8.3 kb

    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, a restricted number of mutations (mostly 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.

    • OPD1. Sequencing of FLNA will identify mutations in all instances with intense clustering in exons 3-5. Mutations in other exons can be found in instances where the clinical phenotype intersects with FMD.
    • OPD2. Sequencing of FLNA will identify most mutations for typical presentations in exons 3-5. Rarely mutations in other exons (11 and 28-29) have been found, especially in instances where female manifestations are more pronounced.
    • FMD. FLNA mutations are widespread throughout the gene in individuals with this diagnosis. Therefore, the most efficient approach is to sequence the entire gene with particular attention paid to exons 3-5, 22, 28-29, and 44-47.
    • MNS. Nearly all females with this diagnosis have mutations identifiable in exon 22. One mutation has been identified in each of exons 6 and 24.

    Table 5. FLNA Pathologic Allelic Variants Discussed in This GeneReview

    Phenotype 1DNA Nucleotide Change
    (Alias 2)
    Protein Amino Acid ChangeReference Sequences
    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.Thr23Alafs*82
    c.1923C>Tp.Tyr643Glyfs*39 3
    Myxomatous cardiac valvular dystrophyg.10807_12749delinsTG
    (1.9-kb deletion)
    p.Val761_Gln942delNT_011726​.13
    Terminal osseous dysplasia with pigmentary skin defectsc.5217G>A 4, 5p.Val1724_Thr1739del NM_001110556​.1

    Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

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

    1. See Genetically Related Disorders.

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

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

    4. All reported cases of this condition have been shown to be 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 mutation appears to define this disorder.

    5. A mutation that predicts no amino acid change but affects splicing resulting in deletion of 16 amino acids [Sun et al 2010]

    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. 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.

    References

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

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    Suggested Reading

    1. 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;103:19836–41. [PMC free article: PMC1702530] [PubMed: 17172441]

    Chapter Notes

    Acknowledgments

    The author is supported by Curekids New Zealand.

    Revision History

    • 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 to live Web site
    • 14 March 2005 (sr) Original submission
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