Table 1.
Summary of BMP4 loss-of-function mutations and patient features
| BMP4 mutationa | Eye | Digit | Brain/neuro | Craniofacial | Growth | Other | Family history | |
|---|---|---|---|---|---|---|---|---|
| Deletionsb | ||||||||
| Patient 1, this study | 2,263-kb deletion (+ 13 genes) | Rieger anomaly, congenital glaucoma microcornea, nystagmus | Hands/feet appear small | Mild gross motor delay with hypotonia; normal brain structures | Macrocephaly, prominent forehead, sunken eyes, small chin, hypoplastic nares | Height and weight ≤3rd centile | SHORT syndrome; hyperextensible joints, teething delay, lipodystrophy, umbilical anomaly | Parents unaffected; mother does not carry deletion; father not tested |
| Patient 2, this study | 158-kb deletion (BMP4 only) | Microphthalmia, persistence of pupillary membrane, high myopia, strabismus, nystagmus, corectopia (right) | WNL | Mild–moderate cognitive impairment, hypotonia; no imaging studies | Maxillary hypoplasia, midface flattening, thin upper lip, broad nasal bridge and tip, telecanthus, preauricular ear tag | WNL | None | Not available |
| Hayashi et al. (2008) | 2,700-kb deletion (+ 17 genes) | Congenital glaucoma, sclerocornea | Bilateral postaxial polydactyly (feet) | Global delay; Decreased brain white matter, lateral ventricular dilatation | Micrognathia | Weight <3rd centile | None | De novo deletion |
| Intragenic mutations | ||||||||
| Patient 3, this study | c.592C>T (p.R198X) | Anophthalmia; microphthalmia with sclerocornea | WNL | Development normal; hydrocephalus, diffuse cerebral atrophy | Facial asymmetry, macrocephaly, large anterior fontanelle | Height >97th centile | Right sided diaphragmatic hernia, laryngomalacia, inguinal hernia | De novo mutation |
| Patient 4, this study | c.171dupC (p.E58RX17) | Anophthalmia | WNL | Development normal; Normal brain structures | Small ears | Height <3rd centile | Small renal cyst (left) | Affected half-sister (Patient 5) and unaffected mother carry the mutation |
| Patient 5, this study | c.171dupC (p.E58RX17); c.362A>G (p.H121R) in trans | Anophthalmia (left), blepharophimosis | Bilateral postaxial polydactyly (hands) | Development normal; normal brain structures | Telecanthus, relative macrocephaly (75th centile), frontal bossing | Height and weight <3rd centile | None | Above; Father not available |
| Bakrania et al. (2008) | c.226delAG (p.S76CfsX29) | Anophthalmia; Microanterior segment, iris and chorioretinal coloboma, retinal dystrophy | Bilateral postaxial polydactyly (feet) | Learning difficulties; hypoplastic corpus callosum, enlarged trigones, sulcal widening | WNL | Not reported | None | Mutation seen in mother, grandmother, and great aunt with polydactyly and/or high myopia |
| Suzuki et al. (2009) | c.592C>T (p.R198X) | Not reported | Not reported | Not reported | Cleft lip and palate | Not reported | Not reported | Parents not tested |
| Lubbe et al. (2011) | c.856C>T (p.R286X) | None | None | None | None | Not reported | Colorectal cancer diagnosed at 42 years | Parents not tested; no first degree relative with colorectal cancer |
aNucleotide numbering is relative to reference sequence NM_001202.3 where +1 is the A of the ATG initiation codon
bPatients with deletion of OTX2 in addition to BMP4 were excluded as OTX2 is a well-established cause of ocular and pituitary defects; therefore, the contribution of BMP4 to the phenotype could not be determined