Discussion

Wolf–Hirschhorn syndrome (OMIM # 194190), also known as Pitt-Rogers-Danks syndrome, is a chromosomal disorder caused by a distal deletion of the short arm of chromosome 4, with loss of the terminal band 4p16.3 which is essential for the full expression of the phenotype [1]. The clinical picture was first described in 1961 by Cooper and Hirschhorn in a child with midline fusion defects, low birth weight, developmental delay, and neonatal-onset seizures [2]. Four years later, Wolf et al. reported a second patient with similar features [3]. These two reports established the existence of human syndromes caused by chromosomal deletions, of which Wolf–Hirschhorn syndrome represents the first recognized example. Its estimated incidence of 1 in 50,000 live births is derived from standard karyotyping, which detects only large 4p16.3 deletions. The introduction of FISH, and later genomic microarrays, improved the detection of small deletions and milder phenotypes, suggesting that historical numbers are likely underestimated and incidence of the syndrome may be 1 in 20,000 [4,5].

Two Wolf–Hirschhorn syndrome critical regions (WHSCR and WHSCR-2) within 4p16.3 contain multiple genes, including WHSC1 (NSD2), LETM1, CPLX1, FGFRL1, and PIGG, which have been investigated for their contribution to different clinical features of the syndrome [4,6-9]. Haploinsufficiency of WHSC1 has been proposed to contribute to the characteristic craniofacial features of the syndrome, whereas hemizygosity of LETM1 has been associated with the occurrence of seizures. However, current evidence indicates that neither gene alone is sufficient to account for these phenotypes, and the contribution of these loci to growth retardation remains inconsistent and somewhat conflicting [8]. As the size of the detectable deletion decreases, the number of associated traits correspondingly declines, supporting the notion that Wolf-Hirschhorn syndrome is a true contiguous gene syndrome rather than the result of a single pleiotropic gene deletion [7]. Genomic rearrangements are mostly de novo (including isolated deletions, unbalanced translocations, inverted duplications, and unbalanced pericentric inversions) but can originate from a balanced parental translocation in 10% to 15% of cases [9]. De novo arrangement tends to be paternal in origin [10]. Due to this genetic heterogeneity, there is significant clinical variability as well. Parents who carry balanced translocations involving 4p16.3 have an increased risk of having offspring with an inherited unbalanced translocation.

There is broad consensus that the postnatal diagnosis of Wolf-Hirschhorn syndrome relies on the association of characteristic facial dysmorphism (prominent forehead, hypertelorism, and wide nasal bridge continuing to the forehead, known as “Greek warrior helmet appearance”), growth retardation, intellectual disability, and seizures or electroencephalographic abnormalities [8]. Zollino et al [8] suggested classification of the syndrome based on the size of the deletion: “mild” (deletions < 3.5 Mb), “classical” (deletions 5–18 Mb), and “severe” forms (deletions > 22–25 Mb).

Most prenatally diagnosed cases show growth restriction, microcephaly, and characteristic craniofacial appearance. The severe early‑onset growth restriction is present in nearly all affected fetuses [11,12] and marked microcephaly persists after birth [13]. The characteristic craniofacial appearance is defined by a prominent glabella, wide nasal bridge with a beaked nose, high forehead, hypertelorism, downturned corners of the mouth, and a short philtrum [14-16]. Based on combined pre‑ and postnatal data, the ultrasound phenotype can be grouped according to its frequency [Table 1] [1]:

Occasionally, Wolf–Hirschhorn syndrome has been diagnosed in the first trimester following the finding of increased nuchal translucency or a cystic hygroma [27,31-33]. Although these early sonographic features are non‑specific and have a wide differential diagnosis, they warrant invasive testing which leads to the diagnosis. 

In our case of prenatally suspected Wolf–Hirschhorn syndrome, diagnosis was made based on characteristic sonographic findings and confirmed by invasive genetic testing. Increased nuchal edema, early fetal growth restriction, and the coexistence of multiple structural abnormalities should raise suspicion for an underlying genetic disorder. Our observations are consistent with previously published prenatal phenotypes of Wolf–Hirschhorn syndrome and support the role of systematic neurosonographic and cardiac evaluation when multiple minor abnormalities are detected. This case highlights the importance of detailed first- and second-trimester ultrasound assessment in detecting complex chromosomal syndromes. 

The prenatal differential diagnosis of Wolf–Hirschhorn syndrome is broad, reflecting the nonspecific nature of its early sonographic findings, most commonly increased nuchal translucency, cystic hygroma, early‑onset fetal growth restriction, and multiple congenital anomalies. These features overlap with several chromosomal and genetic conditions, including trisomy 18 (Edwards syndrome), 11q deletion syndrome (Jacobsen syndrome), Fryns syndrome (particularly when a diaphragmatic hernia is present), Seckel syndrome, VACTERL association, CHARGE syndrome, and Smith–Lemli–Opitz syndrome [1]. This overlap underscores the need for comprehensive evaluation through invasive testing and chromosomal microarray analysis.  

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