Early diagnosis of Wolf–Hirschhorn syndrome triggered by a life‐threatening event: Congenital diaphragmatic hernia

Abstract

Wolf-Hirschhorn syndrome (WHS, OMIM 194190) is a chromosomal disorder characterized by retarded mental and physical growth, microcephaly, Greek helmet appearance of the facies, seizures/epilepsy. Closure defects of lip or palate, and cardiac septum defects occur in 30-50% of cases. Its cause is a deletion in the short arm of chromosome 4. We present a male patient, born after 37 weeks gestation, as the fourth pregnancy of non-consanguineous healthy parents, with unilateral cleft lip and palate, hypertelorism, a right-sided ear tag, and mild epispadias. At age 10 weeks he developed acute respiratory distress and acute bowel obstruction requiring emergency laparotomy. This revealed a left-sided posterolateral diaphragmatic defect, type Bochdalek, with incarceration of the small intestines necessitating major bowel resection. Clinical genetic investigation suggested a chromosome anomaly, but regular karyotyping was normal. However, FISH analysis showed a microdeletion in the short arm of chromosome 4 (4p-), consistent with WHS. A combination of this syndrome with congenital diaphragmatic hernia (CDH) has been rarely described. CDH can present either as an isolated defect at birth, or with multiple congenital abnormalities, or as part of a defined syndrome or chromosomal disorder. Therefore CDH, although not common in WHS, can lead to its diagnosis relatively early in life. We strongly recommend a clinical genetic evaluation of each CDH patient with facial anomalies taking into consideration 4p- deletion syndrome.

Multiple congenital malformations of Wolf-Hirschhorn syndrome are recapitulated inFgfrl1null mice

“…4J,K). The affected laryngeal cartilage elements in Fgfrl1 -/-mice also provide an explanation for the problems in swallowing and speech development in infants with WHS (Battaglia et al, 2001) and, in combination with the diaphragm phenotype, might contribute to respiratory distress (van Dooren et al, 2004).…”

“…Laryngeal cartilage elements in Fgfrl1 -/-mice are significantly reduced in size and provide an explanation for the problems in swallowing and speech development in WHS patients. The fully penetrant diaphragm phenotype of Fgfrl1 -/-mutants might underlie the diaphragmatic hernia observed in some WHS patients (van Dooren et al, 2004) …”

Infants with Bochdalek diaphragmatic hernia: Sibling precurrence and monozygotic twin discordance in a hospital‐based malformation surveillance program

“…Examples of commonly detected abnormalities include trisomy 18, trisomy 21, trisomy 13, tetrasomy 12p, +der 22 t(11;22), 8p-, and 4p- [Pecile et al, 1990;Howe et al, 1996;Faivre et al, 1998;Lurie, 2003;Borys and Taxy, 2004;Tonks et al, 2004;van Dooren et al, 2004]. A recent excellent review demonstrates numerous "hot spots" that may harbor genes contributing to CDH [Lurie, 2003].…”

Retinoid Pathway and Congenital Diaphragmatic Hernia: Hypothesis from the Analysis of Chromosomal Abnormalities

“…Several studies have suggested that 15q24-26 and 8p23.1 are critical for normal development of the diaphragm since recurrent deletions within these regions were associated with CDH [33][34][35][39][40][41][42] . CDH has also been reported in several cases of monosomy 4p16pter associated with WolfHirschhorn syndrome [43][44][45] . Other candidate regions such as 1q41-q42, 6p22-p25, or 22q11 have also been described [23,36,38] .…”