Seckel Syndrome 9

A number sign (#) is used with this entry because of evidence that Seckel syndrome-9 (SCKL9) is caused by homozygous mutation in the TRAIP gene (605958) on chromosome 3p21.

For a general phenotypic description and a discussion of genetic heterogeneity of Seckel syndrome, see SCKL1 (210600).

Clinical Features

Silengo et al. (2001) described 2 Italian sibs with a Seckel-like malformation syndrome characterized by intrauterine growth retardation (IUGR), microcephaly, beaked nose, failure to thrive, and early death. The first sib was a 46,XX girl who at birth underwent surgery for right diaphragmatic hernia. External genitalia appeared normal, with slight clitoral hypertrophy. Other features included micrognathia, low-set ears, hypertrichosis, and clubfeet. She died at age 40 days of respiratory distress. The second sib was a 46,XY infant born with ambiguous external genitalia with urogenital sinus, penile-like clitoris, and underdeveloped labial folds without palpable gonads. Renal sonogram showed bilateral multicystic kidneys, and echocardiography showed atrial and ventricular septal defects. Brain CT revealed microencephaly and pachygyria. The child died at 1 month of age due to respiratory distress. Autopsy showed severe hypoplasia of the pulmonary artery and its branches, large ASD and VSD, enlarged kidneys with multiple calyceal cysts, and pachygyria. Gonads and internal genitalia were not apparent in the pelvis, and serial histologic sections of pelvic soft tissues failed to reveal gonadal tissue or mullerian or wolffian remnants.

Harley et al. (2016) studied 3 unrelated patients with microcephaly, including a female sib of the Italian patients reported by Silengo et al. (2001) and an English and a Turkish boy. All 3 patients had IUGR and substantially reduced postnatal height, with disproportionate microcephaly. All had mild to moderate developmental delay and exhibited similar dysmorphic features, including a long narrow face, micrognathia, and prominent ears. Neuroimaging showed reduced cerebral cortical size and simplified gyri in 2 patients, whereas the third had a slightly enlarged ventricular system. The English boy and the Italian girl had recurrent lower respiratory tract infections, and the girl died of respiratory failure at 10 years of age due to chronic lung disease. The Turkish boy had recurrent urinary tract infections. There was no evidence of immunodeficiency in any of the patients.

Molecular Genetics

In an Italian girl with global growth failure and disproportionate microcephaly from a family originally reported by Silengo et al. (2001), Harley et al. (2016) performed whole-exome sequencing and identified homozygosity for a nonsense mutation in the TRAIP gene (R185X; 605958.0001). Her unaffected parents were heterozygous for the mutation, which was not found in 380 control chromosomes or public variant databases. Sequencing of the TRAIP gene in 262 patients diagnosed with primary microcephaly and primordial dwarfism identified a boy of English ancestry with the same R185X mutation. SNP genotyping was consistent with unrecognized parental relatedness within each family, and haplotype analysis indicated a distant link with shared ancestry between the 2 families many generations earlier, despite their geographic separation. Additional whole-exome sequencing in 28 patients with a presumptive diagnosis of Seckel syndrome identified a Turkish boy who was homozygous for a missense mutation (R18C; 605958.0002) in the TRAIP gene.