the AJMG SEQUENCE
In this issue
MICRODELETION CAUSES WOLF-HIRSCHHORN SYNDROME PHENOTYPE
Hannes et al (p. 996) report that a microdeletion of 600 kb near the Wolf-Hirschhorn critical region (WHSCR) may lead to a subtle Wolf-Hirschhorn syndrome (WHS) phenotype.
Distinctive facial features are a major diagnostic marker of WHS, which can vary clinically and involves moderate to severe intellectual disability, pre- and postnatal growth retardatio n, micro cephaly,seizures, and organ malformations including cleft lip and palate. It is generally accepted that the facial phenotype of Wolf-Hirschhorn syndrome is caused by deletions of either Wolf- Hirschhorn critical regions 1 or 2 (WHSCR1-2).
Figure 3a. Classifications showing face of patient and sibs, respectively.
The researchers identify a 432 kb deletion located 600 kb proximal to both WHSCR1 and WHSCR2 in a patient with a WHS facial phenotype. Genes that underlie this deletion region include FAM193a, ADD1, NOP14, GRK4, MFSD10, SH3BP2, and TNIP2.
A clinical diagnosis of WHS facial phenotype was confirmed by 3D facial analysis using dense surface modeling. Sequencing the Wolf-Hirschhorn syndrome candidate 1 and 2 genes did not reveal any mutations.
The authors suggest the WHSCR1-2 flanking sequence contributes directly or indirectly to the severity of WHS. They hypothesize that either this location harbors regulatory sequences that affect gene expression in the WHSCR1-2 in a defined temporal and spatial developmental window, or the location is additive to deletions of WHSCR1-2, increasing the phenotypic expression.
SMITH-LEMLI-OPITZ FACIAL PHENOTYPE INDICATES OVERALL SEVERITY
The degree of craniofacial abnormality in Smith–Lemli–Opitz syndrome (SLOS) patients is a function of overall severity, suggest Nowacyzk et al (p. 1021).
SLOS, an autosomal recessive condition, results from deficient cholesterol synthesis and has a wide phenotypic spectrum, which includes multiple malformations, distinctive facial appearance, and intellectual disability.
To define the key facial characteristics of patients with SLOS and evaluate evolution of the facial phenotype with age, the researchers did an anthropometric and observational study. Using clinical photographs of 51 patients with SLOS, they took 22 standardized cranial and facial measurements on 42 of the patients and compared these measurements to published age- and sex-matched controls. They then compared craniofacial pattern profiles between sexes, among various age groups, and by physical severity score and plasma cholesterol concentration at the time of diagnosis.
Figure 1. Anthropometric dimensions used in this study. Reproduced from allanson and Cole .
The facial measurements of patients with SLOS had higher deviations from the norm with mean craniofacial variability index (CVI) scores than age- and sex-matched controls. The faces of patients with SLOS were also smaller than controls.
Patients with a lower weight at the time of assessment and patients with higher physical severity score had higher CVI measures, the researchers note.
DIFFERENTIATING BETWEEN PIEBALDISM AND NEUROFIBROMATOSIS TYPE 1 CHALLENGING
Findings by Stevens et al (p. 1196) suggest the need for careful clinical evaluation and molecular testing, if necessary, to distinguish piebaldism from neurofibromatosis type 1 (NF1) and Legius syndrome.
Piebaldism may occasionally include cafe-au-lait macules (CALM) and intertriginous freckling, which may create diagnostic confusion especially in the absence of family history of piebaldism, they write.
Piebaldism is an autosomal dominant disorder characterized by congenital hypopigmented patches of skin and hair and has been found to be associated with mutations in the KIT or SLUG genes. Previous reports describe six patients who were said to have both piebaldism and NF1 because of multiple CALM and intertriginous freckling, but these patients didn't undergo comprehensive NF1 mutation analysis, the researchers note.
They describe a large family with piebaldism, including two members who meet diagnostic criteria for NF1 based on the presence of more than five CALM and intertriginous freckling.
Figure 3. Patient 1. Note CALM and axillary freckling.
The researchers found in several family members affected by piebaldism a novel complex mutation in the KIT gene. The researchers found no NF1 or SPRED 1 mutations in the proband who met diagnostic criteria for NF1.