Clinical and genetic characterization of ten Egyptian patients with Wolf-Hirschhorn syndrome and review of literature

Abstract

Background: Wolf-Hirschhorn syndrome (WHS) (OMIM 194190) is a multiple congenital anomalies/intellectual disability syndrome. It is caused by partial loss of genetic material from the distal portion of the short arm of chromosome.

Methods: We studied the phenotype-genotype correlation.

Results: We present the clinical manifestations and cytogenetic results of 10 unrelated Egyptian patients with 4p deletions. Karyotyping, FISH and MLPA was performed for screening for microdeletion syndromes. Array CGH was done for two patients. All patients exhibited the cardinal clinical manifestation of WHS. FISH proved deletion of the specific WHS locus in all patients. MLPA detected microdeletion of the specific locus in two patients with normal karyotypes, while array CGH, performed for two patients, has delineated the extent of the deleted segments and the involved genes. LETM1, the main candidate gene for the seizure phenotype, was found deleted in the two patients tested by array CGH; nevertheless, one of them did not manifest seizures. The study emphasized the previous.

Conclusion: WHS is a contiguous gene syndrome resulting from hemizygosity of the terminal 2 Mb of 4p16.3 region. The Branchial fistula, detected in one of our patients is a new finding that, to our knowledge, was not reported.

Keywords: WHSCR1; WHSCR2; LETM1 genes; Wolf-Hirschhorn syndrome; cytogenomic analysis.

FIGURE 1

Facial features of the patients showing the Greek warrior helmet, frontal bossing, sparse scalp hair, low set ears, broad nasal bridge, hypertelorism, epicanthic folds, high forehead, proptosis and ectropion. Ptosis in pt. no. 8, 9 & 10; squint in pt. no. 7 & 9; upward eyelid slanting in pt. no. 1, 2, 5, 8 & 10; downward eyelid slanting in pt. no. 3, 6, 7 & 9

FIGURE 2

(a and b) preauricular tag, malformed ear, folded helix (pt. no. 3 & 9). (c) branchial fistula (pt. no. 2). (d) ridged Simian crease (pt. no. 3 & 7). (e) bilateral clinodactyly of the 5th finger (pt. no. 4). (f) overriding toes (pt. no. 4). (g) polydactyly of toes (pt. no. 9). (h) penile hypospadius (pt. no. 3 & 8). (i) clitoromegaly (phallus like) (pt. no. 9)

FIGURE 3

MRI brain showing: (a) Coronal T2‐FLAIR cut showing hypogenesis of corpus callosum and deep white matter dysmyelination (arrow) (pt. no. 7). (b) Saggital T1 showing thin corpus callosum (arrow), axial T1 showing normal posterior fossa (pt. no. 7). (c) Axial T2 showing mild dilatation of lateral ventricles which are separated apart indicating hypogenesis of corpus callosum and deep white matter defective myelination (arrow) (pt. no. 7). (d) Axial T2 and T2 FLAIR showing defective myelination (arrow) (pt. no. 1). (e) Saggital T2 showing thin corpus callosum (hypogenesis) (arrow) (pt. no. 1)

FIGURE 4

FISH (pt. 9 & 10): (a) A GTG banded karyotype showing del(4)(p16.2). (b and c) FISH on a blood metaphase of patients 1 and 2 using LSI WHS probe (red) with 4qter (green) showing only one red signal on one copy of chromosome 4 with deletion in the other copy. (d) FISH on a blood metaphase of patient 10 using 4q subtelomere (red) showing deletion of this region on the ring 4 (arrow)

FIGURE 5

(a and b) MLPA (pt. no. 2 & 3): Ratio chart interpretations of the data by the Coffalyser software showing a heterozygous deletion in WHS region in patients 2 and 3, respectively, indicated by a ratio tending toward 0.5 (arrow), (ratio of 0 would indicate homozygous deletion)

FIGURE 6

array‐CGH (Pt. no. 1): Use of the ChAS software tool with an Affymetrix HD microarray demonstrating a deletion in chromosome 4p. The log2 ratio is equal to 0.5, the CN state is equal to one; and there are only two allele difference tracs indicating terminal deletion of 10.4 Mb, arr[hg19]4p16.3p16.1(68,345_10,465,994)x1