Effect of the size of the deletion and clinical manifestation in Wolf-Hirschhorn syndrome: analysis of 13 patients with a de novo deletion

Abstract

We performed clinical, cytogenetic, and molecular analyses on 13 patients (8 females and 5 males, aged 6 months to 13 years) with Wolf-Hirschhorn syndrome due to de novo deletions of chromosome 4p. All patients presented with the typical facial gestalt, microcephaly, and profound mental retardation. Other clinical signs were low birth weight (10/13; 77%), postnatal short stature (8/12; 66%), muscular hypotonia (12/13; 92%), seizures (11/13; 85%), congenital heart defects (4/13; 31%), colobomata of iris (4/12; 33%), genital anomalies (4/13; 31%), deafness (3/13; 23%), and renal anomalies (3/13; 23%). The smallest deletion was a submicroscopic terminal deletion of nearly 2.5 Mb. The largest was a terminal deletion of nearly 30 Mb. Cleft lip/palate, preauricular pits/tags, and congenital heart defects were present only in patients with terminal deletions larger than 10 Mb. The deviations from mean birth weight, birth length, and postnatal head circumference correlated with the size of the deletion. Determining the parental origin of the deletion with microsatellite markers, the maternal allele was missing in three patients and the paternal allele in eight patients. Our observations support the existence of a partial genotype-phenotype correlation in Wolf-Hirschhorn syndrome.

Fine-grained facial phenotype–genotype analysis in Wolf–Hirschhorn syndrome

“…Wieczorek and co-workers 14 previously reported a correlation in WHS between postnatal head circumference and deletion size. The original aim of this study was to analyse the effects of deletion size on facial morphology in WHS.…”

“…13 There is considerable variation in the phenotypic spectrum, and, more recently, a correlation with the size of the deletion has been recognized; children with submicroscopic deletions within 4p16.3 tend to have a milder phenotype. 14,15 Some patients with microdeletions within 4p16.3 were initially reported as having Pitt-Rogers-Danks syndrome, now considered to be within, and at the milder end of, the WHS spectrum. 16,17 We use small and large, respectively, to refer to a terminal deletion with a break point within 4p16.3, a deletion size of about 3.1 Mb or less, and one with a break point more proximal than 4p16.…”

Wolf-Hirschhorn Syndrome (WHS) – Literature Review on the Features of the Syndrome

“…Death occurs more frequently in patients with larger deletions. It had been proven that the larger deletion, the more severe congenital deformities one presents [1,12,17]. The other congenital defects include muscle hypotonia and urinary tract malformations (such as renal agenesis, oligomeganephronia, bladder exstrophy, cystic dysplasia/hypoplasia and obstructive uropathy) [18].…”

“…It occurs two times more frequently in females [11][12][13]. The more chromosomal material is missing, the larger expression of WHS is observed in patients [7].…”

Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf–Hirschhorn Syndrome

“…Genotype-phenotype correlation studies have shown a relationship between deletion size and severity of clinical presentation. [6][7][8] Of patients meeting the minimal diagnostic criteria, 9 the smallest terminal deletion identified was B1.9 Mb, 1, 9,10 suggesting that genes within this interval of 4p16.3 are responsible for the core features of WHS. 8,11 Beyond this region, the loss of additional critical genes appears to be responsible for variably present features, such as congenital malformations or hearing loss.…”