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.

Wolf-Hirschhorn syndrome revealed by status epilepticus: A case report

“…many cases of metabolic acidosis and malignant hyperthermia are reported in addition to a major risk of gastroesophageal reflux, immune disorder, and hepatic adenomas [16].The differential diagnosis arises with other syndromes associating growth retardation, mental deficiency, and facial dysmorphia: Seckel, CHARGE, Smith-Lemli-Opitz, Opitz G / BBB, Williams, Rett, Angelman and Smith-Magenis. The prognosis is multifactorial; depending on the extent of the deletion [7] the presence of significant chromosomal abnormalities [17], the intensity of the seizures, the presence of associated malformations including cardiac and the extent of mental retardation. The treatment is symptomatic and requires a multidisciplinary approach, including various rehabilitation programs, treatment of epilepsy and nutritional support.…”

Full etiologic spectrum of pediatric severe to profound hearing loss of consecutive 119 cases

“…PVLM is also a common sign of 18q deletion 40 and the developmental insult itself causing PVLM could cause hearing loss 41 , also providing causality between 18q deletion and hearing loss. The hemizygous 4p16.3 deletion has also been proposed to be a molecular genetic cause of SNHL 42 and Wolf–Hirschhorn syndrome 43 . Lastly, an etiologic diagnosis of hearing loss from SB418-819 with a VUS, hemizygous 22q13.3 deletion, mild CND and thinning of the corpus callosum was challenging.…”

Prenatal phenotype of Wolf–Hirschhorn syndrome: A case series and literature review

“…Wolf–Hirschhorn syndrome (WHS) is a congenital malformation syndrome caused by a deletion of the short arm end of chromosome 4 (Maas et al, 2008 ). Its incidence is not less than 1 in 50,000 live births, and the male‐to‐female ratio is approximately 1:2 (Mekkawy et al, 2021 ). The WHS critical region is located at 4p16.3 and is enriched with genes NSD2 ( WHSC1 ), WHSC2 , FGFRL1 , LETM1 , CPLX1 , and PIGG2 (Jiang et al, 2019 ; Mekkawy et al, 2021 ; Sukarova‐Angelovska et al, 2014 ; Yamamoto‐Shimojima et al, 2019 ).…”

“…Its incidence is not less than 1 in 50,000 live births, and the male‐to‐female ratio is approximately 1:2 (Mekkawy et al, 2021 ). The WHS critical region is located at 4p16.3 and is enriched with genes NSD2 ( WHSC1 ), WHSC2 , FGFRL1 , LETM1 , CPLX1 , and PIGG2 (Jiang et al, 2019 ; Mekkawy et al, 2021 ; Sukarova‐Angelovska et al, 2014 ; Yamamoto‐Shimojima et al, 2019 ). The typical facial appearance of WHS is a “Greek warrior helmet” face.…”

“…In addition, WHS is characterized by developmental delays, varying degrees of intellectual impairment, hypotonia (mainly involving the lower extremities), epilepsy or specific electroencephalogram changes, and microcephaly (Mekkawy et al, 2021 ; Simonini et al, 2022 ; Yamamoto‐Shimojima et al, 2019 ). Some patients present with skeletal abnormalities (Buddhdev et al, 2020 ), eye or optic nerve abnormalities (Çelik et al, 2021 ), tumors of various systems (Battaglia et al, 2018 ), dental abnormalities, hearing disorders, heart malformations, cleft lip or palate, urogenital tract malformations, brain structural abnormalities, and digestive system malformations (Mekkawy et al, 2021 ; Simonini et al, 2022 ). Given the lack of effective treatment for WHS, most patients have poor prognosis.…”