Seckel syndrome belongs to the microcephalic osteodysplastic dwarfism group characterized by intrauterine growth retardation, dwarfism, and microcephaly. Characteristics of Seckel syndrome include severe proportionally short stature with severe microcephaly (mean postnatal growth retardation is -7SD with a range from -5 to -13 SD; mean OFC is -9SD with a range from -4 to -14SD), a ‘bird like’ profile include a receding forehead, large eyes, beak-like protusion of the nose, narrow face, receding lower jaw and micrognathia, and mental retardation. A number of Seckel-like syndromes have been identified including microcephalic osteodysplastic primordial dwarfism, type II (MOPDII) which is differentiated from Seckel syndrome by more severe growth retardation, radiological abnormalities, and absent or mild mental retardation. The radiological abnormalities in MOPDII are short limbs with preferential distal involvement, coxa vara, epiphysiolysis and metaphyseal flaring with V-shaped distal femora metaphyses.
In addition to having a wide phenotypic range, Seckel syndrome has also been shown to be genetically heterogeneous, with five loci mapped to date (SCKL1-5). Of these five loci, three disease genes including ATR, CENPJ and CEP152, have been reported to cause Seckel syndrome in a small number of families (O’Driscoll et al, 2008; Al-Dosari et al, 2010; Kalay et al, 2011).
Interestingly, mutations in CENPJ and CEP152 are also implicated in autosomal recessive primary microcephaly. Based on this overlapping molecular mechanism, the relationship between primary microcephaly and Seckel syndrome warrants further elucidation.
Mutations in PCNT (pericentrin; OMIM#605925) have been identified in patients with MOPDII. Rauch et al. (2008) identified 29 different homozygous or compound heterozygous mutations in the PCNT gene in 25 patients with MOPDII. Willems et al (2010) identified 12 homozygous and 1 heterozygous mutation in the PCNT gene in 8/8 patients with MOPDII and 5/16 patients diagnosed with Seckel syndrome. Clinical analysis of Seckel cases with PCNT mutations showed that they all presented with minor skeletal changes and clinical features compatible with a MOPDII diagnosis, although the significant overlap between the two conditions was acknowledged. This illustrates the difficulty of clinically distinguishing MOPDII and Seckel syndrome and points to the potential likelihood that they may represent the same disorder with a wide clinical spectrum. As more patients with MOPDII and Seckel syndrome are tested for mutations in the PCNT gene, a better understanding of genotype-phenotype correlation may emerge.
The University of Chicago Genetic Services laboratory offers full gene sequencing of PCNT as well as a Tier 2 Seckel syndrome panel. This panel includes full gene sequencing for the ATR, CENPJ and CEP152 genes.
References: Al-Dosari, MS, et al. Novel CENPJ mutation causes Seckel syndrome. (2010) J. Med. Genet. 47 :411-414; Kalay, E. et al. CEP152 is a genome maintenance protein disrupted in Seckel syndrome. 2011. Hum Genet. 122:23-32; O’Driscoll, M et al. A splicing mutation affecting expression of ataxia-telangiectasa and Rad3-related protein (ATR) results in Seckel syndrome. (2003) Nature Genet. 33:497-501; Rauch, A et al., Mutations in the pericentrin (PCNT) gene cause primordial dwarfism. (2008) Science. 319:816-819; Willems, M. et al., Molecular analysis of pericentrin gene (PCNT) in a series of 24 Seckel/microcephalic osteodysplastic primordial dwarfism type II (MOPDII) familes. (2010) J Med Genet. 47:797-802.