A highly distinct constellation of findings first reported by Holmes and Schepens (1972)
has withstood the test of time. Furthermore, the recent identification of the genetic basis of this disorder may afford insights in causation of its component malformations (Kantarci et al., 2007
Donnai-Barrow syndrome and FOAR syndrome, herein referred to as DB/FOAR syndrome, is a unique malformation complex. Based on this review of published cases the core features of this syndrome consist of:
- Congenital anomalies found in ≥90%: hypertelorism; partial or complete agenesis of the corpus callosum; enlarged anterior fontanelle; characteristic facial features;
- Functional anomalies found in ≥90%: proteinuria; high myopia, sensorineural hearing loss; developmental delay; and
- Anomalies found in ~50%: congenital diaphragmatic hernia and omphalocele/umbilical hernia; additional features such as coloboma and macrocephaly also appear to occur in ~50% of cases, but the numbers are too small to state this with certainty.
Based on data tabulated from the currently small number of cases, the combined presence of the features listed in items 1 and 2 appear highly suggestive of the diagnosis of DB/FOAR syndrome, as no other syndrome matches this constellation. Several conditions have partial overlap with DB/FOAR syndrome and may be considered in the differential diagnosis as discussed below. However, the full spectrum of DB/FOAR syndrome may become broader over time because of several factors, including availability of LRP2 mutation analysis, increased number of cases with a confirmed diagnosis, and decreased bias in publishing only the cases that are most severely affected.
Craniofrontonasal syndrome (CFNS, OMIM 304110) is an X-linked condition caused by mutations in the gene EFNB1. Overlapping features include hypertelorism, downslanting palpebral fissures, frontal bossing, umbilical hernia, agenesis of the corpus callosum, and congenital diaphragmatic hernia. Features that distinguish CFNS from DB/FOAR syndrome include coarser facial features, craniosynostosis, bifid nasal tip, thick and wiry hair, and a variety of limb anomalies including brachydactyly, syndactyly, and longitudinally grooved nails. Females with CFNS are more severely affected than males.
Chudley McCullough (OMIM 604213) and Acrocallosal (OMIM 200990) syndromes are each autosomal recessive disorders with agenesis of the corpus callosum, macrocephaly, and developmental delay. Patients also demonstrate sensorineural hearing loss, or hypertelorism and polydactyly, respectively. However, neither condition includes the additional functional deficits of myopia and proteinuria, nor do they include omphalocele/umbilical hernia and/or diaphragmatic hernia.
Generating the differential diagnosis surrounding the presence of a congenital diaphragmatic hernia, Fryns (OMIM 229850) and Pallister-Killian (OMIM 601803) syndromes should be considered as they show partial overlap with DB/FOAR syndrome. However, the characteristic constellation of structural and functional deficits is not recapitulated in either of these disorders.
The presence of low molecular weight proteinuria is not restricted to DB/FOAR syndrome but more typically occurs along with other renal tubular abnormalities as in Dent disease 1 (OMIM 30009), which is caused by mutations in a chloride channel gene. Two related disorders with proteinuria are Dent disease 2 (OMIM 300555) and Lowe syndrome (OMIM 300535) due to mutations in the gene OCRL1. Although Lowe syndrome patients can have multi-system anomalies involving the ocular, dental, and central nervous systems, the specific anomalies in these organ systems differ from those found in DB/FOAR syndrome.
Mutations in the gene LRP2
are responsible for DB/FOAR syndrome. An LRP2
targeted gene deletion mouse was initially generated and characterized in 1996 (Willnow et al., 1996
). Homozygous null pups showed craniofacial anomalies (including microophthalmia, shortened nose, agenesis of the corpus callosum, and dysplasia of the olfactory bulbs), and low molecular weight proteinuria. The vast majority of LRP2
null mice died of “respiratory insufficiency” in the perinatal period. Remarkably, the pattern of anomalies in both mice and humans is consistent with the distribution of expression of LRP2
during development, though the knock out mouse phenotype does not completely recapitulate the human phenotype (in that the mice demonstrate microophthalmia, a finding not observed in DB/FOAR patients).
The gene LRP2
encodes megalin, a large single-spanning transmembrane glycoprotein that serves as a multiligand endocytotic receptor. Megalin is highly expressed on the apical surface of absorptive epithelia in the developing brain and spinal cord, optic cup, otic placode, and developing renal system (Assemat et al., 2005
; Wicher and Aldskogius, 2008
). In the mature kidney, megalin is intensely expressed in the renal proximal tubule and its lack of normal expression in patients with DB/FOAR syndrome and in megalin knockout mice accounts for the low molecular weight proteinuria (Christensen and Birn, 2002
). Megalin is also expressed in thyrocytes, lung buds, and reproductive tract (as reviewed in Fisher and Howie, 2006
). Megalin performs reuptake of numerous ligands including retinol binding protein, vitamin D binding protein, and a variety of lipoproteins (Christensen and Birn, 2002
), and it is possible that more await discovery. Failure to re-uptake one or more of these compounds, particularly at a critical time in development and/or possibly in a tissue-specific manner, might contribute to the structural and functional abnormalities that typify DB/FOAR syndrome. A direct signaling role for megalin has also been postulated for a few of its ligands.
Although the widespread distribution of megalin during development accounts for much of the DB/FOAR phenotype, the mechanisms responsible for the fact that omphalocele/umbilical hernia and congenital diaphragmatic hernia each are found in only 50% of patients remain unclear. Their variable presence raise the possibility that “two-hits” are required for their appearance, the first being functional insufficiency of megalin and the second being a modifier gene or genes and/or an environmental cue. For example, failure to reuptake vitamin A in the preurine resulting in subphysiologic concentrations has gained traction as a plausible hypothesis, in light of several lines of evidence suggesting an important role for the retinoic acid pathway in normal diaphragm development (Kling and Schnitzer, 2007
The occurrence of brain and craniofacial abnormalities, both cardinal features in DB/FOAR syndrome patients and in megalin knockout mice, underscores the importance of megalin in the developing nervous system. During murine development, megalin is expressed in the apical surface of the neuroepithelium at E9.5 (Willnow et al., 1996
), where it may directly mediate endocytosis of molecules from the amniotic fluid before neural tube closure (Fisher and Howie, 2006
). Deficient or dysfunctional megalin may also perturb endogenous signaling, particularly the Shh/BMP4
and retinoic acid pathways (McCarthy and Argraves, 2003
). Though the full role of megalin in Shh/BMP4
signaling is not elucidated, available evidence from megalin knockout mice demonstrates defective Shh/BMP4
signaling and impaired patterning of the ventral telencephalon in the developing central nervous system (Spoelgen et al., 2005
The discovery that LRP2 mutations are responsible for the DB/FOAR syndrome unifies two entities once considered distinct, and also draws attention to an important developmental pathway during embryogenesis. This finding also raises the question whether more subtle changes in LRP2 function can cause or contribute to isolated malformation components of DB/FOAR syndrome, such as agenesis of the corpus callosum or congenital diaphragmatic hernia.