Craniosynostosis with Ectopia Lentis and a Homozygous 20-base Deletion in ADAMTSL4

Craniosynostosis with ectopia lentis has been described five times since 1950 with unknown inheritance and variable phenotype. The patient was diagnosed with right coronal synostosis at age 10 weeks requiring surgery, and bilateral ectopia lentis with high myopia at 10 months. No other family member was affected. There is no known consanguinity within the family. Genetic screening ruled out FBN1, TGFBR2, and the known craniosynostosis hotspots (FGFR2 exon 8 and exon 10 and FGFR3 exon 6) as the cause. A homozygous deletion in exon 6 of ADAMTSL4 (c.767_786del 20) that has been shown to cause isolated ectopia lentis was found. The mutation results in a premature termination codon (p.Gln256ProfsX38). The proband’s mother, father and one sibling are heterozygous carriers of the mutation. This is the first detailed report of a possible genetic determinant of craniosynostosis with ectopia lentis. Although this mutation causes isolated ectopia lentis, this may be evidence of pleiotropic effects of ADAMTSL4 and may represent an overlapping syndrome with a causative mutation in ADAMTSL4. These findings need to be confirmed in further cases with craniosynostosis and ectopia lentis.

[1]  Jason C. Ho,et al.  ADAMTSL4, a secreted glycoprotein widely distributed in the eye, binds fibrillin-1 microfibrils and accelerates microfibril biogenesis. , 2012, Investigative ophthalmology & visual science.

[2]  A. Rump,et al.  A homozygous microdeletion within ADAMTSL4 in patients with isolated ectopia lentis: evidence of a founder mutation. , 2011, Investigative ophthalmology & visual science.

[3]  T. Fiskerstrand,et al.  A novel ADAMTSL4 mutation in autosomal recessive ectopia lentis et pupillae. , 2010, Investigative ophthalmology & visual science.

[4]  E. Jabs,et al.  Genetic basis of potential therapeutic strategies for craniosynostosis , 2010, American journal of medical genetics. Part A.

[5]  D. Charteris,et al.  Role of ADAMTSL4 mutations in FBN1 mutation‐negative ectopia lentis patients , 2010, Human mutation.

[6]  H. Dollfus,et al.  Confirmation of ADAMTSL4 mutations for autosomal recessive isolated bilateral Ectopia Lentis , 2010, Ophthalmic genetics.

[7]  S. Leal,et al.  A homozygous mutation in ADAMTSL4 causes autosomal-recessive isolated ectopia lentis. , 2009, American journal of human genetics.

[8]  J. Hurst,et al.  Clinical dividends from the molecular genetic diagnosis of craniosynostosis , 2006, American journal of medical genetics. Part A.

[9]  E. Haan,et al.  FBN1, TGFBR1, and the Marfan‐craniosynostosis/mental retardation disorders revisited , 2006, American journal of medical genetics. Part A.

[10]  M. Hurley,et al.  FGF and FGFR signaling in chondrodysplasias and craniosynostosis , 2005, Journal of cellular biochemistry.

[11]  B. Källén,et al.  Maternal Drug Use, Fertility Problems, and Infant Craniostenosis , 2005, The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association.

[12]  D. Güven,et al.  Craniosynostosis and ectopia lentis in a propositus whose parents are cousins (Am J Med Genet (Early View)) , 2005, American journal of medical genetics. Part A.

[13]  G. Shaw,et al.  Fertility treatments and craniosynostosis: California, Georgia, and Iowa, 1993-1997. , 2003, Pediatrics.

[14]  J. Cruysberg,et al.  Craniosynostosis associated with ectopia lentis in monozygotic twin sisters. , 1999, American journal of medical genetics.

[15]  H. Dietz,et al.  Mutation in fibrillin-1 and the Marfanoid-craniosynostosis (Shprintzen-Goldberg) syndrome , 1996, Nature Genetics.

[16]  C. Bonaïti‐pellié,et al.  Genetic study of nonsyndromic coronal craniosynostosis. , 1995, American journal of medical genetics.

[17]  J. Wiggs,et al.  Oxycephaly, bilateral ectopia lentis, and retinal detachment. , 1992, Annals of ophthalmology.

[18]  A. Teebi,et al.  Craniosynostosis, ectopia lentis, and congenital heart defects: further delineation of an autosomal dominant syndrome with incomplete penetrance. , 2002, American journal of medical genetics.

[19]  E. Green,et al.  Mutations in TWIST, a basic helix–loop–helix transcription factor, in Saethre-Chotzen syndrome , 1997, Nature Genetics.

[20]  Verger,et al.  [Craniofacial dysostosis with displacement of the crystalline lens]. , 1950, Archives francaises de pediatrie.