Background

Wolf-Hirschhorn syndrome (WHS) is a well-defined disorder due to variable size-deletions of the chromosomal region 4p16.3, characterized by a clinical picture encompassing growth restriction, developmental delay, microcephaly, congenital hypotonia and major malformations, including midline, heart, renal and skeletal defects, along with the typical facial gestalt, consisting of the so called “Greek warrior helmet” appearance (high forehead, continuing to a wide nasal bridge, with short philtrum, high arched eyebrows, hypertelorism, and micrognathia). Seizures occur in nearly all affected patients within the age of 3 years and complicate the management, acting as a significant prognostic factor for the final degree of intellectual disability.

In front of the great phenotypic variability of WHS, depending mostly on the extent of the 4p deletion, the core WHS phenotype is conventionally defined by the association of intellectual disability, growth delay, facial gestalt and seizures [1]. Thus, two minimal critical regions responsible for WHS (WHSCR) have been identified, corresponding to the smallest region, whose haploinsufficiency determines the core phenotype [2,3,4].

More recently, exome sequencing analyses identified two genes within the WHSCR, whose loss-of-function variants contribute to a clinical spectrum consistent with atypical or partial WHS: WHS candidate gene 1 (WHSC1), also known as Nuclear receptor-binding Set Domain-protein 2 (NSD2), contained only partly within the WHSCR [5], and WHS candidate gene 2 (WHSC2), also known as Negative Elongation Factor Complex Member A (NELFA), entirely contained within the WHSCR [6].

We describe a patient with a de novo variant of NSD2 and discuss the clinical implications.

Case presentation

The proband was a 6-year-old boy, born at 34 weeks of gestation by cesarean section from healthy, non-consanguineous parents. Gestation was complicated by intrauterine growth restriction (IUGR) and the baby displayed low birth weight. The neonatal period was characterized by hypotonia, followed by psychomotor delay. No episodes of seizure were reported.

At physical examination, he displayed marphanoid habitus, muscle hypotrophy and facial dysmorphisms consisting in high frontal hairline, upslanting palpebral fissures and full lips with bifid ugula (Fig. 1). Cryptorchidism, shawl scrotum, mild clinodactyly of the right little finger, bilateral syndactyly of the II and III toes with sandal gap and a small café-au-lait spot on dorsum were also noted. The radiographic essay demonstrated delayed bone age and echocardiography showed mild mitral prolapse.

Fig. 1
figure 1

Patient’s facies, characterized by high frontal hairline, upslanting palpebral fissures and full lips

Full size image

Both single nucleotide polymorphism-arrays and next-generation intellectual disability gene panel proved negative. Whole genome sequencing analysis revealed a heterozygous de novo variant of NSD2 (c.2523delG).

Discussion and conclusions

NSD2 acts as a histone methyltransferase, responsible for the methylation of HEK36, thus explaining the occurrence of developmental delay in carriers of NSD2 variants, in light of the crucial role of histones modification in brain development. Of note, the description of two patients with intact NSD2, exhibiting clinical features resembling WHS but only mild developmental delay [7], has lead to the assumption that the haploinsufficiency of NSD2 is responsible for the developmental delay, typically observed in WHS patients; this hypothesis has been further supported by the documentation of a higher degree of developmental delay in patients with disrupted NSD2, compared with those with the intact gene [8, 9]. Autism spectrum disorder has been reported in eight NSD2-haploinsufficient children [10, 11]. Moreover, deletions of NSD2 are considered responsible for the facial gestalt of WHS, in light of the observation of non-specific findings consistent with WHS (growth and developmental delay) but without the typical dysmorphic features, in several patients with microdeletions sparing NSD2 [12, 13].

Hence, the clinical spectrum of NSD2 deletion encompasses: prenatal and postnatal growth restriction [14], microcephaly, developmental delay [15], congenital heart defects and several phenotypic traits, including hypertelorism, upward-slanting palpebral fissures, prominent nasal bridge, abnormal teething and micrognathia. Cleft palate has been described in fourteen patients [16,17,18,19,20,21]. Compared to WHS patients, NSD2-deleted children tend to display a milder spectrum of skeletal abnormalities, usually consisting of clinodactyly [22]. Table 1 summarizes the previously reported cases of NSD2 haploinsufficiency. Remarkably, seizures are not usually part of the clinical spectrum of NSD2 variants.

Table 1 Summary of previous published cases of NSD2 haploinsufficiency
Full size table

LETM1 (Leucine zipper/EF-hand containing transmembrane), involved in calcium signaling and mapping within the WHSCR, had been previously identified as responsible for seizures. However, this assumption has recently been questioned by the observation of the occurrence of seizures in children carrying terminal 4p deletions sparing LETM1, and of the lack of seizure in individuals with interstitial deletions including LETM1, but preserving a relatively large terminal 4p segment [23]: these observations suggest that the haploinsufficiency of LETM1 alone may not be sufficient in causing seizures, which would rather result from the effect of additional candidate genes [24].

Remarkably, the recurrence risk of NSD2 variants is 50% and must be taken into account when counseling families of affected individuals.

In conclusion, full WHS phenotype probably arises from the cumulative effect of the combined haploinsufficiency of several causative genes mapping into the 4p16.3 region, as a contiguous genes syndrome, with slightly different phenotypes depending on the specific genes involved in the deletion [25].

NSD2 haploinsufficiency is responsible of a distinctive entity, with clinical findings falling to some extent within the WHS phenotype, but not sufficient to allow a conclusive diagnosis of WHS.

When evaluating children with pictures resembling WHS, clinicians should bear this condition in mind as a possible differential diagnosis.