Balkan Journal of Medical Genetics

PHENOTYPIC VARIATIONS IN WOLFHIRSCHHORN SYNDROME
Sukarova-Angelovska E, Kocova M, Sabolich V, Palcevska S, Angelkova N
*Corresponding Author: Doz. Elena Sukarova-Angelovska, Pediatric Clinic, Medical Faculty, Vodnjanska 17, 1000 Skopje, Republic of Macedonia. Tel.: +389-70358582. Fax: +389-22439301. E-mail: Esukarova@doctor.com
page: 23

DISCUSSION

Most WHS cases described in the older literature have sizeable terminal deletions with full blown clinical presentation of WHS. Advanced molecular techniques [FISH, comparative genomic hybridiztion (CGH)] provide the possibility of detecting smaller deletions with less evident phenotypes. Since it is a contiguous gene syndrome, variable numbers of genes contribute to the phenotype in each patient. The spectrum of clinical manifestation of WHS is highly variable, including specific facial dysmorphism, growth and mental delay. In the cases described in the literature, severity of the clinical presentation has been associated with the size of the deleted region and the breakpoint site. However, there are some reports that patients with similar deletions still show clinical variability. Thus, other mechanisms are suspected, mutations in modifier genes outside the deleted region, postzygotic mutational events, gene silencing [4], and/ or unmasked recessive mutations by a deletion [22]. Sometimes phenotypic variability and severity of the clinical manifestation do not correlate with the size of the deletion. Estabrooks et al. [23] pointed out that all his described cases shared the same phenotype, although the length of the deleted region was different. In his cases, the severity of the clinical presentation and greater number of dysmorphic features were not correlated with the amount of the deleted genes. However, all had deletion of the WHCR within the deleted segment. Our study confirms the hypothesis in the literature that the length of the deleted region is crucial to the severity of the phenotype [24,25]. Clinical assessment in our cohort of patients was based upon the number and severity of the separate facial features, as well as upon the presence of organ malformations. Three of the patients with pronounced phenotypes had a cytogenetically visible deletion of the short arm of chromosome 4. Patient 1 had the most severe clinical presentation and most extensive deletion beginning from band p15.3. Patient 3, except for characteristic features, had a cleft lip/palate and patient 4 had only a cleft palate, which indicates that the deleted region in both patients exceeds the WHCR. Cleft lip/palate has been described in the literature in cases with larger deletions centromeric to the WHCR [10]. Since the probe for FISH that we used does not include part of the chromosome 4p centromeric to WHCR, we could not confirm this result in patients 3 and 4. In patients 4 and 5, the diagnosis was suspected due to the obvious phenotype of WHS, and the diagnosis was established with a FISH probe for WHCR. However, the presence and severity of minor dysmorphic features, as well as other malformations, was less pronounced than in the group with apparent cytogenetically visible deletions. In some studies where microdeletions have been studied, cardiac anomalies were not found. In patients 4 and 5, however cardiac anomalies were present, which can be explained by other underlying mechanisms [10]. Although not severely affected, the cases with microdeletions in variable parts of the WHCR, can broaden genotypephenotype studies. Some features described in our cases have not been reported previously such as intestinal malrotation including both small and large intestines in patient 1, or unusual complex cardiac malformation in patient 5. Patient 6 with a mosaic deletion had less evident clinical presentation with facial features only reminiscent of a classical WHS phenotype accompanied with a moderate mental retardation. This is in accordance with the reported cases in the literature where different percent of mosaic cell lines were found together with severe mental retardation [12,13]. All our patients showed prenatal and postnatal growth delay and delayed developmental milestones. There was some discordance between cytogenetic findings and mental retardation (for example, patient 4 had microdeletions and pronounced motor and mental disability). However, it can be explained by the frequency and severity of the seizures and administration of potent antiepileptic drugs. Four of our patients had seizures, and the youngest one (patient 5) (now at the age of 5 months) had a specific EEG consistent with dysrhythmic action, but without apparent seizures so far. Seizures were of different pattern, generalized, unilateral and myoclonic outbursts, as reported elsewhere [5]. The outbursts were difficult to control despite combined anticonvulsive therapy. Seizures are the most frequent cause of death in these patients.

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