Seckel Syndrome 1

A number sign (#) is used with this entry because Seckel syndrome-1 (SCKL1) is caused by homozygous or compound heterozygous mutation in the ATR gene (601215) on chromosome 3q23.

Description

Seckel syndrome is a rare autosomal recessive disorder characterized by intrauterine growth retardation, dwarfism, microcephaly with mental retardation, and a characteristic 'bird-headed' facial appearance (Shanske et al., 1997).

Genetic Heterogeneity of Seckel Syndrome

Other forms of Seckel syndrome include SCKL2 (606744), caused by mutation in the RBBP8 gene (604124) on chromosome 18q11; SCKL4 (613676), caused by mutation in the CENPJ gene (609279) on chromosome 13q12; SCKL5 (613823), caused by mutation in the CEP152 gene (613529) on chromosome 15q21; SCKL6 (614728), caused by mutation in the CEP63 gene (614724) on chromosome 3q22; SCKL7 (614851), caused by mutation in the NIN gene (608684) on chromosome 14q22; SCKL8 (615807), caused by mutation in the DNA2 gene (601810) on chromosome 10q21; SCKL9 (616777), caused by mutation in the TRAIP gene (605958) on chromosome 3p21; and SCKL10 (617253), caused by mutation in the NSMCE2 gene (617246) on chromosome 8q24.

The report of a Seckel syndrome locus on chromosome 14q, designated SCKL3, by Kilinc et al. (2003) was found to be in error; see History section.

Clinical Features

This condition was given the 2 names bird-headed dwarfism and nanocephaly by Virchow. Seckel (1960) produced the definitive publication based on 2 personally observed cases and 13 reliable plus 11 less reliable cases from the literature. In addition to dwarfism of 'low birth weight' type, the features are small head, large eyes, beak-like protrusion of the nose, narrow face, and receding lower jaw. Mental retardation is not as marked as might be expected in view of the very small brain. Multiple occurrence in the same sibship, increased frequency of parental consanguinity, occurrence in both sexes, and normal parents suggest autosomal recessive inheritance. Affected sisters were reported by Black (1961). Harper et al. (1967) reported brother and sister who strikingly resembled Seckel's cases 1 and 2, 2 other reported cases, and the 3 sibs reported by McKusick et al. (1967). Majewski and Goecke (1982) picked out 17 cases that agreed with Seckel's case 1 and 43 others (including the cases of McKusick et al., 1967) that they felt were not identical to that case. Butler et al. (1987) raised the question of whether there may be a subgroup of Seckel syndrome patients who have chromosome instability and/or hematologic problems. Chromosome breakage was demonstrated in 2 patients, one of whom had pancytopenia. Sugio et al. (1993) suggested that only 19 patients with classic Seckel syndrome had been reported--17 reviewed by Majewski and Goecke (1982) and 2 reported by Butler et al. (1987). They reported a Japanese case in which severe brain dysplasia was present.

Hayani et al. (1994) described a female who was diagnosed with Seckel syndrome at 2 years of age. She was dwarfed (at 26 years of age she weighed 14.8 kg and was 113 cm tall), had severe microcephaly, and was mentally retarded. At age 26 years, she was diagnosed with acute myeloid leukemia (AML) by the study of blood marrow and peripheral blood. Chemotherapy produced severe toxicity with profound bone marrow aplasia. She died 2 months later. Although some patients with Seckel syndrome manifest anemia and other hematologic abnormalities, AML had not previously been reported. Hayani et al. (1994) suggested that patients with Seckel syndrome may be at risk of developing myelodysplasia and AML.

Shanske et al. (1997) reported a family of Yemeni-Arab extraction in which 3 sibs out of 8, the offspring of consanguineous parents, had this disorder. Imaging studies of the central nervous system were reported. Shanske et al. (1997) stated that only 6 families with 2 or more children affected with this disorder had previously been reported; however, they appeared to have overlooked the family reported by McKusick et al. (1967) with 3 affected sibs. In that family, neuroimaging studies were not performed but detailed anatomical studies of the brain at autopsy were reported.

In 2 unrelated Arabic patients with Seckel syndrome, Abou-Zahr et al. (1999) tested for hematologic abnormalities and chromosome breakage, suggesting Fanconi anemia. By Western analysis, they determined the expression of FAA (607139) and FAC (227645), 2 Fanconi anemia disease gene products that together account for approximately 80% of Fanconi anemia, and found that they were expressed at similar levels to those of normal cell lines. Furthermore, the cells from the patients were resistant to the effects of mitomycin C.

In a consanguineous Pakistani family, Goodship et al. (2000) found that the proband with Seckel syndrome weighed 1.1 kg at birth, with a head circumference of 24 cm. At age 9 years his height was 106 cm and head circumference 37 cm. He had moderate mental retardation and did not walk until the age of 7 years. He had striking microcephaly, receding forehead, and micrognathia with a prominent nose. The teeth were crowded, with dental malocclusion.

Seckel syndrome shows phenotypic overlap with type II microcephalic osteodysplastic primordial dwarfism (MOPD2; 210720). Both are characterized by intrauterine growth retardation, severe proportionate short stature, and microcephaly; MOPD2 is distinct from SCKL by more severe growth retardation, radiologic abnormalities, and milder mental retardation.

Can et al. (2010) reported a male infant with characteristic features of Seckel syndrome, who also had tetralogy of Fallot, ventricular septal defect, pulmonary stenosis, patent foramen ovale, left arcus aorta, dextroposition of the aorta, and increased intraventricular septal thickening. The authors stated that although cardiac malformation has previously been described in patients with Seckel syndrome, this was the first case involving tetralogy of Fallot.

Ogi et al. (2012) reported 2 unrelated English patients with Seckel syndrome-1 resulting from compound heterozygous mutations in the ATR gene (601215.0004 and 601215.0005). The patients had severe microcephaly (-10 SD), micrognathia, dental crowding, and small ears with absent lobes. Skeletal anomalies were also prominent, including symmetric dwarfism, small/poorly ossified patellae, and clinodactyly or small tapering fingers. Brain imaging of 1 patient showed an area of abnormal gyration and hypoplastic corpus callosum.

Mokrani-Benhelli et al. (2013) described a 9.5-year-old French girl who had intrauterine growth retardation and dwarfism at birth, with severe microcephaly and mental retardation that worsened with age. Examination revealed a triangular face, high-set slightly beaked nose, micrognathia, upslanting palpebral fissures, thick eyebrows with synophrys, slightly posteriorly rotated ears lacking lobes, and a narrow palate. Her hands were thin and flat with abnormally positioned thumbs. She had pes cavus with retracted toes, and a growth disorder of the nails. Puberty occurred early. Radiography revealed right convex lumbar scoliosis, slight dorsal kyphosis, and hyperlordosis; in addition, her long bones were very slender. She had severe anemia at birth, which after initial transfusions spontaneously corrected and was normal thereafter. There was no obvious immunologic defect, but analysis of immunoglobulin class switch recombination (CSR) junctions resulting from in vivo class switching between S-mu and S-alpha-1 regions showed a significant decrease in blunt-end joining and an increased usage of microhomology (MH) at the S-mu/S-alpha-1 switch junctions in patient cells compared to controls. This increase in MH-mediated CSR junctions suggested a defect in a DNA repair factor involved in the CSR process.

Mapping

Goodship et al. (2000) studied 2 consanguineous families with Seckel syndrome from the same village in Pakistan who were not known to be related to each other. By a genome screen and homozygosity mapping, they assigned the Seckel syndrome locus to 3q22.1-q24, between loci D3S1316 and D3S3710; maximum lod score = 8.72. All 5 affected individuals were homozygous for the same allele.

Heterogeneity

Faivre et al. (2002) confirmed the heterogeneity of Seckel syndrome by excluding the previously mapped loci on chromosomes 3 and 18 in 5 consanguineous and 1 multiplex nonconsanguineous Seckel syndrome families.

Molecular Genetics

O'Driscoll et al. (2003) showed that affected individuals in the Pakistani families studied by Goodship et al. (2000) had a mutation in the gene encoding ataxia-telangiectasia and RAD3-related protein (ATR; 601215.0001).

In a 9.5-year-old French girl with Seckel syndrome, Mokrani-Benhelli et al. (2013) identified compound heterozygosity for a missense mutation in the ATR gene (D1879Y; 601215.0003) and a 540-kb deletion on chromosome 3 encompassing ATR as well as 3 other genes, XRN1 (607994), PLS1 (602734), and TRPC1 (602343). Her unaffected parents were each heterozygous for 1 of the mutations.

Associations Pending Confirmation

For discussion of a possible association between Seckel syndrome and variation in the ATRIP gene, see 606605.0001.

Animal Model

Murga et al. (2009) developed a mouse model of Seckel syndrome by replacing exons 8, 9, and 10 of the mouse Atr gene with those from human, and then introducing the A-to-G transition in exon 9 into the humanized gene (601215.0001). ATR Seckel homozygous mice were born at submendelian ratios and showed severe dwarfism that was already noticeable at birth. Mutant placentas showed an accumulation of necrotic areas and overall loss of cellularity. In addition to the overall dwarfism, Seckel mice showed microcephaly and facial dysmorphism including micrognathia and receding foreheads. Seckel mice also had small brains, cysts, and agenesis of the corpus callosum. Seckel mice showed high levels of replicative stress during embryogenesis, when proliferation is widespread, but this was reduced to marginal amounts in postnatal life. In spite of this decrease, adult Seckel mice showed accelerated aging, which was further aggravated in the absence of p53 (191170). Murga et al. (2009) concluded that their results supported a model whereby replicative stress, particularly in utero, contributes to the onset of aging in postnatal life, and this is balanced by the replicative stress-limiting role of the checkpoint proteins ATR and p53.

History

Kilinc et al. (2003) performed linkage analysis by a microsatellite genome scan in a study of 13 unrelated Turkish families with Seckel syndrome and identified a novel locus (SCKL3) on chromosome 14q in 5 of the families. In an erratum, the authors stated that this finding was incorrect and that one of the families they had studied was found to have a mutation in the LIG4 gene (601837). In their original article, the authors noted that there was great variation in the phenotypes of the patients in the 5 'linked' families.