Dental developmental abnormalities in a patient with subtelomeric 7q36 deletion syndrome may confirm a novel role for the SHH gene

Abstract

Studies in mice demonstrated that the Shh gene is crucial for normal development of both incisors and molars, causing a severe retardation in tooth growth, which leads to abnormal placement of the tooth in the jaw and disrupted tooth morphogenesis. In humans the SHH gene is located on chromosome 7q36. Defects in its protein or signaling pathway may cause holoprosencephaly spectrum, a disorder in which the developing forebrain fails to correctly separate into right and left hemispheres and that can be manifested in microforms such as single maxillary central incisor. A novel role for this gene in the developing human primary dentition was recently demonstrated. We report a 12-year old boy with a de novo 7q36.1-qter deletion characterized by high-resolution karyotyping, oligonucleotide aCGH and FISH. His phenotype includes intellectual disability, non-verbal communication, hypospadia, partial sacral agenesis and absence of coccyx, which are distinctive features of the syndrome and mainly correlated with the MNX1, HTR5A and EN2 genes. No microforms of holoprosencephaly spectrum were observed; but the patient had diastema and dental developmental abnormalities, such as conical, asymmetric and tapered inferior central incisors. The dental anomalies are reported herein for the first time in subtelomeric 7q36 deletion syndrome and may confirm clinically a novel role for the SHH gene in dental development.

Case Report: Congenital Brain Dysplasia, Developmental Delay and Intellectual Disability in a Patient With a 7q35-7q36.3 Deletion

“…In this study, we report a heterozygous 9.4 Mb microdeletion of 7q35-q36.3 (chr7:147,493,985-156,774,460) in a 2.5-year-old boy with congenital brain dysplasia, developmental delay, and intellectual disability. The findings of our study are consistent with those of previous studies and report that microdeletion in the 7q terminal may lead to abnormal brain and facial structures, developmental delay, and intellectual disability (Linhares et al, 2014;Busa et al, 2016).…”

Clinical Phenotypes Associated to Engrailed 2 Gene Alterations in a Series of Neuropediatric Patients

“…There are few series studies reporting EN2 and MR association ( Laroche et al, 2008 ), although it seems to be universally spread among single case reports ( Sarnat et al, 2002 ; Titomanlio et al, 2005 ). In our study, as mentioned before, all the EN2-g patients suffered from some intellectual disability, ranging from severe to mild MR, in agreement to the described phenotype in 7q terminal deletion syndrome where EN2 gene is affected ( Frints et al, 1998 ; Linhares et al, 2013 ). Moreover, axonal guidance in target territories to establish adequate synaptic patterning depend of engrailed proteins concentration ( Marie and Blagburn, 2003 ); then, decreasing of EN2 transcription could represent a haploinsufficient phenotype that predispose to MR and ASD in 7q terminal deletion syndrome.…”

“…These structural alterations may be explained by abnormal development of the mid-hindbrain neural tube segment. In addition, brain anomalies due to the EN2 haploinsufficiency have been also proposed as a cause of mental retardation in 7q terminal deletion syndrome ( Frints et al, 1998 ; Linhares et al, 2013 ). Although these experimental and clinical data support the importance of the EN2 protein function in brain development, to date no studies have been published to try to establish an association between clinical and cerebral structural phenotypes and abnormalities in EN2 gene expression.…”

Defects in intervertebral disc and spine during development, degeneration, and pain: New research directions for disc regeneration and therapy

“…Shh is a key regulator of embryonic patterning, and continues to regulate the components of the postnatal disc (Figure 4). Point mutations in SHH and BRA cause vertebral defects in humans including defects in the formation of caudal vertebrae and sacral agenesis (Fontanella et al, 2016;Ghebranious et al, 2008;Horn et al, 2004;Linhares et al, 2014;Postma et al, 2014;Vargas et al, 1998). This indicates the translational importance of SHH and BRA in disc formation and maintenance.…”