8p inverted duplication/deletion syndrome (ORPHA:96092)
A rare chromosomal anomaly clinically characterized by mild to severe intellectual disability, severe developmental delay (psychomotor and speech development), hypotonia with tendency to later develop progressive hypertonia, and characteristic facial features. The main congenital anomalies associated include central nervous system (CNS) malformations such as hypoplasia/agenesis of the corpus callosum (80%), skeletal abnormalities such as scoliosis/kyphosis or dislocated hips (60%), and congenital heart defects (25%).
Epidemiology
About 60 patients have been reported. Whilst epidemiological data is limited, the prevalence at birth has been estimated between 1/10,000-30,000 in Europe.
Clinical description
The most common clinical manifestations include developmental delay, mild to severe degree of cognitive deficit, lack or delay of expressive speech and language and hypotonia, contributing to a mild-severe global developmental delay. Most children with invdupdel(8p) have been reported to be happy natured, sociable and communicative albeit non-verbal, but some may exhibit attention deficits, impulsivity and hyperactivity. In this view, it has been also estimated that between thirty to fifty percent of individuals with invdupdel(8p) may develop a neurodevelopmental disorder during infancy. Facial dysmorphism, more noticeable in childhood, is subtle and frequently includes a prominent forehead, temporal baldness, anteverted nostrils, eversion of the lower lip, large mouth and ears and a short neck. Adults with invdupdel(8p) have height ranging from normal to exceptionally tall, and have a tendency to develop progressive hypertonia, spastic quadriplegia and orthopedic conditions like contracted joints and scoliosis. Albeit, a wide range of congenital malformations (such as cardiac defects, eye and urinary system anomalies) and other skeletal abnormalities have also been reported, the most common congenital malformation being corpus callosum hypoplasia/agenesis.
Etiology
The invdupdel(8p) consists of a deletion distal to the 8p23 region followed by an intermediate intact segment, and a proximal inverted duplication of various extensions. These rearrangements are mediated mainly by two olfactory receptor gene clusters or defensin repeat (ORDRs) at the breakpoints; the polymorphic 8p23 inversion between these clusters increases the susceptibility on 8p to rearrangements. Thus, the inverted duplication with a terminal deletion of the short arm of chromosome 8 mostly occurs as either an inverted duplication from centromere to D8S552 with a pter deletion from D8S349 or as an inverted duplication from 8p11.2 or 8p21 to D8S552, with a telomeric deletion from D8349. To date, all invdupdel(8p) occurred de novo, but the inversion allele is frequently found in one of the parents, and has an estimated allele frequency of 27% in the general Japanese population.
Diagnostic methods
Diagnosis is based on clinical manifestations and agenesis of the corpus callosum on brain magnetic resonance imaging (MRI) leading to chromosomal analysis. Molecular techniques (FISH, MLPA, CGH array) can be used for the genetic characterization of the above-mentioned rearrangements.
Differential diagnosis
Differential diagnosis includes other multiple congenital anomalies/intellectual deficit syndromes such as Trisomy 8p, in particular those carrying an 8p21-p22 duplication.
Antenatal diagnosis
Antenatal diagnosis is based on ultrasound detection of fetal abnormalities (e.g. agenesis of corpus callosum) and cytogenetic analysis after amniocenteses or chorionic villus sampling.
Genetic counseling
Genetic counseling is recommended. Invdupdel(8p) rearrangements occur de novo; however, parents can carry a harmless common inversion involving the 8p23.1 segment (prevalence 1/4 to 1/5) which on rare occasions might lead to the more complex invdupdel(8p) rearrangement in their offspring.
Management and treatment
Physiotherapy from an early age as well as occupational therapy and speech therapy are recommended. Some patients benefit from music therapy. No gross orthopedic complications are noted. However, regular follow-up is needed.
Prognosis
There is no report on life expectancy. The majority of invdupdel(8p) individuals will need lifelong, full-time care. Spastic quadriplegia may be slowly progressive with age.

                            Last update: 
                            April 2021


                            - Expert reviewer(s): 
                            Dr Andrea BARTULI | ITHACA* - Dr Marina MACCHIAIOLO | ITHACA* - Dr Davide VECCHIO | ITHACA*


                                * European Reference Network