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 a pregnancy at increased risk are possible.

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).

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.

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.

Treatment of Manifestations

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.

Surveillance

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

Mode of Inheritance

Donnai-Barrow syndrome (DBS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are usually obligate heterozygotes (i.e., carriers of one LRP2 pathogenic variant).
• Paternal uniparental isodisomy for chromosome 2 accounted for homozygous LRP2 pathogenic variants in a proband whose father was heterozygous for the variant and whose mother had two normal LRP2 alleles [Kantarci et al 2008] (see Table 6).
• Heterozygotes (carriers) are asymptomatic in that they do not manifest structural birth defects, craniofacial dysmorphology, or kidney dysfunction.

Sibs of a proband

• When both parents are carriers of an LRP2 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.
• Given the variability among affected sibs of the occurrence of major structural birth defects (i.e., omphalocele or CDH), the presence of one of the defects in one sib does not predict the presence of either or both in another sib.
• In the case of uniparental isodisomy (see Table 6), the recurrence risk for sibs of the proband is very low.
• Heterozygotes (carriers) are asymptomatic in that they do not manifest structural birth defects, craniofacial dysmorphology, or kidney dysfunction.

Offspring of a proband. No reports of reproduction in individuals with DBS have been published.

Other family members. When a parent of the proband is a carrier of a pathogenic variant, each of his/her sibs is at a 50% risk of being a carrier.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the LRP2 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic 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 of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the LRP2 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Fetal ultrasonography. Prenatal diagnosis using ultrasound examination or fetal MRI scanning for pregnancies at increased risk for DBS can be achieved by detecting anomalies such as partial or complete agenesis of the corpus callosum, diaphragmatic hernia, omphalocele, and the characteristic facial appearance including ocular hypertelorism and prominent eyes. However, failure to detect these structural birth defects in a pregnancy at increased risk for DBS does not eliminate the possibility of an affected fetus.

Molecular Pathogenesis

Donnai-Barrow syndrome (DBS) is caused by loss-of-function pathogenic variants in LRP2, which encodes the low-density lipoprotein receptor-related protein 2, an endocytic transmembrane glycoprotein also referred to as megalin or LRP-2/gp330. Megalin is widely expressed in specialized absorptive epithelia [Willnow & Christ 2017].

Many features of DBS are recapitulated in animal models of megalin deficiency; for example:

• Forebrain anomalies, including agenesis of corpus callosum and mild holoprosencephaly (not reported in individuals with DBS) [Christ et al 2016]
• Enlarged and exophthalmic eyes (buphthalmos) [Storm et al 2014]
• Glaucoma or glaucomatous changes in some but not every model [Veth et al 2011, Cases et al 2015, Christ et al 2015]
• Defects of cardiovascular development, specifically of the outflow tract and the atrioventricular canal [Baardman et al 2016] (The incidence of heart defects in individuals with DBS may be underestimated [Pober et al 2009].)

Megalin is required for endocytosis [Anzenberger et al 2006, Fisher & Howie 2006]. Dozens of megalin ligands have been identified (reviewed in Christensen & Birn 2002]). Increased excretion of vitamin D-binding protein (VDBP), retinol-binding protein (RBP) [Kantarci et al 2007], cubilin, and type 3 carbonic anhydrase (CAIII) as in Dent's disease [Dachy et al 2015] have been reported in humans with DBS. Megalin is also necessary for the CYP27B1-mediated activation of 25-hydroxyvitamin D to 1,25 dihydroxyvitamin D in the renal proximal tubule, and for its regulation by CYP24A1-mediated inactivation [Nykjaer et al 1999, Chapron et al 2018]. Deficiencies manifested as hypovitaminosis D and osteomalacia have been described in a few individuals [Storm et al 2013, Anglani et al 2018].

Gene structure. LRP2 spans approximately 236 kb of genomic DNA and contains 79 coding exons (NM_004525.2). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Twenty-two pathogenic or likely pathogenic variants have been documented in 17 kindreds [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, Khan & Ghazi 2018]. Typically, pathogenic and likely pathogenic variants are distributed throughout the gene and are unique to each kindred. The homozygous or compound heterozygous LRP2 variants include small deletions or insertions and conserved splice site, nonsense, and missense variants inherited from each heterozygous carrier parent. As a rare event, one affected individual was homozygous for an LRP2 pathogenic variant resulting from paternal isodisomy of chromosome 2; the father was a heterozygous carrier of c.11469_11472delTTTG [Kantarci et al 2008].

Normal gene product. The 600-kd megalin protein comprises 4655 amino acids. Megalin is a member of the low-density lipoprotein receptor gene family, which is expressed predominantly in apical surface of absorptive or secretory epithelia. A variety of tissues including the brain, eye, renal proximal tubule, lung, intestine, uterus, oviduct, male reproductive tract, and embryonic yolk sac express megalin. Megalin binds more than 50 ligands, including lipoproteins, vitamin-binding proteins, hormones, enzymes, and immune- and stress-response-related proteins. It has been proposed that megalin interacts with the sonic hedgehog protein (reviewed in Christ et al [2016]). Megalin and a membrane receptor cubilin (gp280) share many ligands [Fisher & Howie 2006].

Abnormal gene product. The pathogenic variants in LRP2 that cause DBS result in absent or nonfunctional megalin protein. The c.2639+1G>A splice variant was shown to result in complete absence of megalin staining in proximal tubular cells [Storm et al 2013], supporting the loss of function hypothesis. Weak and diffuse cytoplasmic staining was detected in the kidney biopsy of an individual who was compound heterozygous for the c.7564T>C and c.12623C>A LRP2 variants [Dachy et al 2015]. Based on this observation, one or both missense variants are likely to result in a trafficking defect and/or protein instability. In the same tissue sample, the normal apical signal of cubilin at the brush border of the proximal tubule was not affected, suggesting that processing of megalin and cubilin is at least partially independent.

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Acknowledgments

We thank Dr Patricia K Donahoe for her leadership and continuous support. We also thank the many physicians who referred patients with DBS/FOAR to us. Finally, we gratefully thank all families who have participated in our study, through which we were able to find the gene responsible for DBS/FOAR.

Author History

Dian Donnai, MD (2008-present)
Sibel Kantarci, PhD, FACMG (2008-present)
Mauro Longoni, MD (2018-present)
Kristin M Noonan, MD; Medical College of Wisconsin (2008-2018)
Barbara R Pober, MD (2008-present)

Revision History

• 21 November 2018 (sw) Comprehensive update posted live
• 28 June 2011 (me) Comprehensive update posted live
• 28 August 2008 (me) Review posted live
• 28 April 2008 (brp) Original submission