Donnai-Barrow Syndrome
Summary
Clinical characteristics.
Donnai-Barrow syndrome (DBS) is characterized by typical craniofacial features (large anterior fontanelle, wide metopic suture, widow's peak, markedly widely spaced eyes, enlarged globes, downslanted palpebral fissures, posteriorly rotated ears, depressed nasal bridge, and short nose. Ocular complications include high myopia, retinal detachment, retinal dystrophy, and progressive vision loss. Additional common features include agenesis of the corpus callosum, sensorineural hearing loss, intellectual disability, and congenital diaphragmatic hernia and/or omphalocele. Both inter- and intrafamilial phenotypic variability are observed.
Diagnosis/testing.
The diagnosis of DBS is established in a proband with: the characteristic clinical features and a distinctive pattern of low-molecular-weight proteinuria; and/or biallelic pathogenic variants in LRP2 identified by molecular genetic testing.
Management.
Treatment of manifestations: Surgical repair of diaphragmatic hernia and/or omphalocele; corrective lenses for myopia; preventive treatments for retinal detachment; hearing aids and/or cochlear implants for hearing loss; antiepileptic drugs for seizures; supplementation as needed for low serum vitamins A and D; education tailored to degree of intellectual, visual, and hearing abilities.
Surveillance: Ophthalmologic surveillance to monitor for retinal detachment; serial audiologic examinations; serial measurement of renal function including blood urea nitrogen and serum creatinine concentrations, urinalysis, and serum vitamin A and D; monitor developmental progress and educational needs.
Genetic counseling.
DBS is inherited in an autosomal recessive manner. In general, the parents of an affected child are obligate heterozygotes with each carrying one pathogenic variant; one instance of uniparental disomy has been reported. When both parents are known to be carriers of a pathogenic variant, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. If the pathogenic variants in the family are known, carrier testing for at-risk relatives and prenatal testing of pregnancies at increased risk are possible.
Diagnosis
Suggestive Findings
Donnai-Barrow syndrome (DBS) should be suspected in individuals with the following clinical and radiographic features. No single clinical feature is pathognomonic for DBS, nor have diagnostic criteria been formalized.
Clinical features
- Characteristic facial features (see Figure 1):
- Large anterior fontanelle in infants and young children
- Wide metopic suture in infants and young children
- Widow's peak
- Widely spaced eyes, typically marked
- Enlarged globes leading to the appearance of prominent eyes
- Downslanted palpebral fissures
- Posteriorly rotated ears
- Depressed nasal bridge
- Short nose with broad or bifid tip
- Ophthalmologic abnormalities. High myopia (-6 diopters or worse), retinal detachment (30%), retinal dystrophy and optic nerve hypoplasia, progressive visual loss, iris coloboma or iris hypoplasia in some individuals
- Sensorineural hearing loss. Onset in infancy or childhood (100%)
- Developmental delay. Almost always present
- Omphalocele (or umbilical hernia) (~40%)
- Diaphragmatic hernia (or eventration) (~40%)
Figure 1.
Facial characteristics over time in the same male with Donnai-Barrow syndrome A. At age six months; broad forehead, markedly widely spaced eyes, left iris coloboma, and short nose
Radiographic features. Agenesis of corpus callosum (complete or partial)
Establishing the Diagnosis
The diagnosis of Donnai-Barrow syndrome (DBS) is established in a proband with the characteristic clinical features and a distinctive pattern of low-molecular-weight proteinuria and/or biallelic pathogenic variants in LRP2 identified by molecular genetic testing (see Table 1).
Biochemical Testing
Absent or abnormally functioning megalin, the protein encoded by LRP2, prevents normal renal proximal tubule reuptake of megalin ligands, resulting in excess spillage of proteins with low molecular weight in the urine in 100% of individuals with DBS. Among proteins identified by urinary protein electrophoresis* are:
- Retinol-binding protein (RBP)
- Vitamin D-binding protein (VDBP)
*Note: The use of a "dipstick" is not an adequate substitute to protein electrophoresis to identify megalin ligands in the urine of individuals with DBS.
Molecular Genetic Testing
Molecular genetic testing approaches can include gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of DBS has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of DBS, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of LRP2 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.Note: As LRP2 is among the longest genes in the human genome and contains several private benign variants, extreme caution must be used in interpreting sequence changes. The use of an interpretative framework (e.g., the published guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology) is recommended [Richards et al 2015].
- A multigene panel that includes LRP2 and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of DBS is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Donnai-Barrow Syndrome
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| LRP2 | Sequence analysis 3 | 17/17 families 4, 5 |
| Gene-targeted deletion/duplication analysis 6 | None reported |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Kantarci et al [2007], Kantarci et al [2008], Stora et al [2009], Shaheen et al [2010], Storm et al [2013], Schrauwen et al [2014], Dachy et al [2015], Khalifa et al [2015], Anglani et al [2018].
- 5.
One affected individual was homozygous for an LRP2 pathogenic variant resulting from paternal isodisomy of chromosome 2 (see Molecular Genetics) [Kantarci et al 2008].
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Clinical Characteristics
Clinical Description
The following information is based on case reports reviewed in Patel et al [2007], Pober et al [2009], Shaheen et al [2010], Roane et al [2012], Storm et al [2013], Dachy et al [2015], Anglani et al [2018], and Khan & Ghazi [2018].
Craniofacial features.Widely spaced eyes, depressed nasal bridge, short nose with a broad and occasionally indented tip, broad forehead, and prominent parietal frontal bossing are characteristic findings and are consistently present in individuals with DBS and confirmed biallelic LRP2 pathogenic variants. Downslanted palpebral fissures and low-set posteriorly angulated ears are very frequent findings. While some of these features may change over time, the facial gestalt remains characteristic in the few reported adults.
Ophthalmologic abnormalities. Progressive visual loss resulting in legal blindness is common and seemingly the result of severe myopia and an attendant risk for retinal detachment, although prompt treatment can improve the chances of useful vision. Retinal detachment can be unilateral or bilateral, complete or partial, and can occur in young children. Prophylactic treatment with peripheral barrier photocoagulation to prevent retinal detachment has been successful in several individuals. Progressive retinal dystrophy has been observed in a few individuals; the exact nature and rate of progression of the retinal dystrophy remain to be determined. Optic nerve hypoplasia has been reported in at least one individual. The combination of a small and recessed optic nerve head, surrounded by multiple rings of abnormal pigmentation masking the neuroretinal rim, and the presence of multiple thin vessels emanating from the optic disk was proposed as a characteristic finding on fundoscopy. Iris coloboma, frequently bilateral or affecting the right eye, is common and often present alongside hypoplastic iris stroma. Glaucoma and cataracts have only rarely been reported
Sensorineural hearing loss. Profound bilateral sensorineural hearing loss is frequently acquired and diagnosed in early childhood. Despite a relative paucity of data, it appears that hearing can deteriorate over time, but not every individual progresses to complete loss. Some individuals have useful hearing using hearing aids and seven reported individuals have successfully received cochlear implants (see Deafness and Hereditary Hearing Loss Overview for definitions).
Renal disease. The majority of individuals with DBS present with asymptomatic low-molecular weight proteinuria (LMWP). In the adult kidney, megalin is highly expressed in proximal tubules where it plays a key role in the reuptake of several proteins by receptor-mediated endocytosis. The characteristic urinary protein profile can be detected by Coomassie staining of a random urine sample. Increased excretion of vitamin D-binding protein (VDBP) and retinol-binding protein (RBP) are consistent with the presence of DBS and may lead to hypovitaminoses in some individuals. Urinary loss of VDBP and RBP, however, are not specific to DBS and may be present in individuals with tubular dysfunction. Urinary cubilin and its ligands are detectable in urine samples of individuals with DBS. Hypercalciuria, nephrocalcinosis, nephrolithiasis, and focal segmental glomerulosclerosis have been reported. Progression to nephropathy and end-stage renal disease is a rare but life-threatening complication, especially in adults, and urinary function should be monitored in individuals with DBS. One of the first reported individuals died of renal failure at age 30 years. No renal phenotype has been convincingly documented in individuals with a heterozygous LRP2 pathogenic variant.
Developmental delay, intellectual disability, and behavioral features. Motor milestones are only slightly delayed and most children become continent. No systematic studies of intellectual functioning exist, but available data suggest that all individuals with DBS have intellectual disabilities of varying degrees ranging from mild to moderate. Formal assessment is difficult because of the severe vision and hearing deficits. Roane at al [2012] described a child age five years engaging in self-injurious behavior that was responsive to behavioral therapy; however, self-injurious behavior is not typically observed in individuals with DBS. Teenagers and young adults attend school with special provisions for hearing and vision problems. Some communicate using sign language, and can perform routine tasks and retain a variable degree of independence. An adult individual reportedly suffered from psychosis since childhood. Mood swings and depressive symptoms in this individual were compatible with her diagnosis of schizoaffective disorder. Overall, interactions with her were described as pleasant. She did not exhibit deterioration of cognitive or functional abilities beyond what was caused by her co-occurring psychiatric disorder but she did not live independently.
Diaphragmatic hernia (or eventration) and/or omphalocele (or umbilical hernia) are each reported in approximately 40% of affected individuals. The two defects infrequently occur together [Gripp et al 1997, Kantarci et al 2007, Patel et al 2007]. The absence of either or both does not exclude the diagnosis.
Seizures. A few individuals have developed tonic-clonic seizures in childhood or adolescence. In one individual, the first episode of seizures developed into status epilepticus leading to her demise. No single antiepileptic drug has been demonstrated to be the treatment of choice specifically for this disorder, and therapy should follow standard guidelines.
Growth. Relatively high birth weight (~4 kg) has been recorded in several infants. Macrocephaly is present in many individuals with DBS and it is often apparent at birth. Height and weight eventually appear to be within the normal range but a few of the older children are tall, with heights on the 90th centile.
Neuroimaging. Agenesis of corpus callosum, either complete or partial, is reported in most individuals with DBS (see Figure 2). The presence of additional brain anomalies, such as periventricular nodular heterotopia and abnormalities of gyral patterns, is increasingly appreciated.
Figure 2.
MRI in a female age three years demonstrates numerous abnormalities including hypogenesis of the corpus callosum (most notably involving the rostrum and splenium) (long white arrow), partially empty sella turcica (S), and small pons (P).
Other. Involvement of other organ systems (e.g., ventriculoseptal defect, bicornuate uterus) has been reported but is rare. Pubertal development occurs at the appropriate times.
Prognosis. Information on long-term follow up and natural history of DBS is limited to a few individuals because many affected pregnancies are interrupted or result in perinatal death secondary to congenital malformations. Major risks are due to complications of retinal detachment leading to visual loss in individuals already compromised by hearing defects, and progression of renal dysfunction. Only two adults older than age 50 years with molecularly confirmed LRP2 pathogenic variants have been reported [Stora et al 2009, Anglani et al 2018].The most notable health concern is deteriorating renal function, resulting in renal transplantation in one individual and renal rickets in the other.
Genotype-Phenotype Correlations
No genotype-phenotype correlations are known.
Nomenclature
Donnai-Barrow syndrome (DBS) [Donnai & Barrow 1993] and faciooculoacousticorenal (FOAR) syndrome [Holmes & Schepens 1972, Schowalter et al 1997] were reported as two distinct entities, although overlapping clinical features were appreciated [Devriendt et al 1998, Chassaing et al 2003]. It is now known that these syndromes represent the same clinical entity and are caused by pathogenic variants in LRP2 [Kantarci et al 2007].
The following terms should no longer be used when referring to DBS:
- Syndrome of ocular and facial anomalies, telecanthus, and deafness
- Holmes-Schepens syndrome
- Diaphragmatic hernia-exomphalos-hypertelorism syndrome
- Diaphragmatic hernia-hypertelorism-myopia-deafness syndrome
Prevalence
No population-based incidence or prevalence data are available. Only 49 individuals with sufficient clinical and/or molecular data to establish the diagnosis of DBS have been reported in the medical literature. Many of these individuals are members of a few large consanguineous families.
DBS has been reported in different ethnic groups, including northern and central European, Middle Eastern, American of European origin, and African American. No one ethnic group predominates.
Differential Diagnosis
Donnai-Barrow syndrome (DBS) is associated with congenital diaphragmatic hernia (CDH) (see Congenital Diaphragmatic Hernia Overview).
Table 2.
Disorders to Consider in the Differential Diagnosis of Donnai-Barrow Syndrome
| Differential Diagnosis Disorder | Gene(s) | MOI | Clinical Features of This Disorder | |
|---|---|---|---|---|
| Overlapping w/DBS | Distinguishing from DBS | |||
| Pallister-Killian syndrome (12p tetrasomy mosaicism) (OMIM 601803) | N/A | Sporadic |
|
|
| Fryns syndrome | Unknown | AR |
|
|
| Chudley-McCullough syndrome (OMIM 604213) | GPSM2 | AR |
|
|
| Acrocallosal syndrome (OMIM 200990) | KIF7 | AR |
| Preaxial or postaxial polydactyly, occasionally syndactyly |
| Dent disease 1, Dent disease 2 1, Lowe syndrome | CLCN5 OCRL | XL | Low molecular-weight proteinuria |
|
| Craniofrontonasal syndrome (OMIM 304110) | EFNB1 | XL |
|
|
| Stickler syndrome | COL2A COL9A1 COL9A2 COL9A3 COL11A1 COL11A2 2 | AD AR |
|
|
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance; N/A = not applicable; XL = X-linked
- 1.
Clinical and biochemical overlap has been proposed between these conditions and DBS
- 2.
Heterozygous pathogenic variants in COL11A2 are associated with Stickler syndrome without ocular features.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Donnai-Barrow syndrome (DBS), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with Donnai-Barrow Syndrome
| System/Concern | Evaluation | Comment |
|---|---|---|
| Eyes | Ophthalmologic evaluation | Frequent, detailed ophthalmologic exams to assess visual acuity & retinal integrity |
| ENT | Audiologic evaluation | Serial evaluation to monitor progression/degree of hearing loss |
| Neurologic | Neuroimaging | Preferably MRI |
| EEG | If symptoms of seizure disorder are present | |
| Renal | Serum blood urea nitrogen (BUN), serum creatinine, & urinalysis | To assess renal function |
| Serum vitamin A & vitamin D (25-hydroxyvitamin D) | Hypovitaminosis D & osteomalacia have been reported. Both 25-hydroxyvitamin D3 & 1,25-dihydroxyvitamin D3 are megalin ligands. Megalin is necessary for activation of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 in the renal proximal tubule. | |
| Miscellaneous/ Other | Developmental evaluation | Developmental testing appropriate for degree of vision & hearing impairments |
| Consultation w/clinical geneticist &/or genetic counselor |
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with Donnai-Barrow Syndrome
| Manifestation/ Concern | Treatment | Considerations/Other |
|---|---|---|
| Diaphragmatic hernia | Surgical repair 1 | Postoperative assessment of respiratory function to determine if there is ↑ risk for long-term respiratory problems |
| Omphalocele | Surgical repair 1 | |
| Myopia | Corrective lenses | Peripheral laser photocoagulation may minimize the risk of retinal detachment resulting from high myopia. |
| Retinal detachment | Treatment as per ophthalmologist | |
| Hearing loss | Hearing aid &/or cochlear implant per ENT | |
| Seizures | Standardized treatment w/AEDs by experienced neurologist | Many different AEDs may be effective; no one AED has been shown effective specifically for this disorder. |
| Hypovitaminoses | Supplementation as needed | Monitoring of serum vitamins A & D (25-hydroxyvitamin D) |
AEDs = antiepileptic drugs; ENT = ear, nose, and throat (specialist)
- 1.
Surgical repair of omphalocele and/or diaphragmatic hernia appears to pose no greater risk than repair of these defects in children with other genetic syndromes.
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Developmental Disability / Intellectual Disability Management Issues
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the United States, early intervention is a federally funded program available in all states.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.
Ages 5-21 years
- In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
- Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
- Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
- Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.
Social/Behavioral Concerns
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavioral management strategies or providing prescription medications, such as medication used to treat attention deficit hyperactivity disorder, when necessary. Repetitive self-injurious behavior has been reported in a single individual [Roane et al 2012] and psychosis in another [Stora et al 2009] (see Clinical Description).
Surveillance
Table 5.
Recommended Surveillance for Individuals with DBS
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Eyes | Ophthalmologic evaluation | Per ophthalmologist & determined by findings present |