Seckel syndrome phenotype in a live-born with ring 4/monosomy 4 chromosomal mosaicism

Abstract

This is the second report of the Seckel syndrome phenotype in a patient with a ring 4 chromosome. The proband was identified through prenatal growth restriction at 34 weeks gestation, which prompted an amniocentesis. The karyotype was 46, XX. r(p?q?35) [8] / 45, XX, -4 [12]. At 38 weeks gestation a female infant was born, after an otherwise uncomplicated pregnancy. She was severely SGA in all parameters, with a weight of 1030 grams. The Apgar scores were low, and respiratory problems required endotracheal intubation. She had significant hypotonia and microcephaly with a sloping forehead and bitemporal narrowing. The facial features were characteristic of Seckel syndrome, including down-slanted palpebral fissures, a prominent nose with a broad nasal tip, a small mouth with a thin upper lip, and micro-retrognathia. The ears were small, low set, and posteriorly rotated. She also had abnormal palmar creases, a cleft palate, and hypoplastic labia. Postnatal study of peripheral blood lymphocytes confirmed the karyotype as 46, XX, r(4)(p16q35) (24) / 45, X, -4 [4]. After discontinuation of the ventilator at age 18 days, she remained tachypneic on supplemental oxygen. Feeding difficulties were encountered and nasogastric feeds were instituted. Her weight gain was modest and at 33 days of life her weight was 1332 grams.According to the literature, r(4) patients phenotypically resemble Wolf-Hirschhorn syndrome. Co-existence of a r(4) chromosome with the Seckel syndrome phenotype was reported only once previously (Anderson CE et al: Am.J.Med.Genet. 72:281-5.1997). To explain this association, we are postulating that the locus of the Seckel syndrome gene might be on the distal arm of chromosome 4. In this scenario, a mutation of the gene on the normal chromosome 4, combined with the deletion of a normal allele on the r(4), could explain the co-existence of Seckel syndrome and r(4) in these 2 cases. Molecular analyses of the deleted regions of chromosome 4 in classical Seckel syndrome patients may be warranted to prove that the association is not coincidental. Alternatively, the mosaic monosomy 4 (which has not been described previously in a liveborn infant) could be causing the severe growth retardation. It is less likely that this could explain the typical facial features of Seckel syndrome.