Koolen–De Vries syndrome

Presentation

The symptoms associated with this syndrome are variable, but common features include: low birthweight, low muscle tone at birth, poor feeding in infancy (often requiring feeding by tube for a period) and oromotor dyspraxia together with moderate developmental delays and learning disabilities but amiable behaviour. Other clinically important features include epilepsy, heart defects (atrial septal defect, ventricular septal defect) and kidney/urological anomalies. Silvery depigmentation of strands of hair have been noted in several patients. With age, there is an apparent coarsening of facial features.

17q21.3 was reported simultaneously in 2006 by three independent groups, with each group reporting several patients, and is now recognised to be one of the more common recurrent microdeletion syndromes. In 2007, a patient with a small duplication in same segment of DNA was described. An overview of the clinical features of the syndrome, by reviewing 22 individuals with a 17q21.31 microdeletion, estimated the disorder is present in 1 in every 16,000 people.

Genetics

The recurrent deletion is between 500 and 650 kilobases (Kb) in size encompassing at least six genes, among them the microtubule-associated protein tau (MAPT). A review of five patients found the parental chromosome from which the deletion originated carried a common 900kb inversion polymorphism. The orientation of low copy repeats flanking the deleted segment suggests the inversion in the parental chromosome influences the deletion in the child's chromosome via a non-allelic homologous recombination (NAHR) mechanism.

Affected genes

The deletion that causes this disease can remove up to six different genes. These include:

• The uncharacterized protein C17orf69 (also known as FLJ25168).
• The protein SPPL2c, putative intramembrane-protease, member of the presenilin-homologues, the SPP/SPPL-proteases
• Corticotropin releasing hormone receptor 1 (CRHR1, also known as CRF-R, CRF1)
• Microtubule-associated protein tau (MAPT)
• The uncharacterised protein KIAA1267 (also known as DKFZP727C091, KANSL1)

Diagnosis

Diagnosis is established with a chromosome microarray analysis. The symptoms of Koolen–de Vries syndrome can be very variable, and there is no single clinical sign required to establish the diagnosis.

Treatment

Treatment centres around the symptoms in each individual and can include: early physiotherapy for feeding and motor problems, physiotherapy for strengthening the muscles, speech therapy, sign language, alternative or augmentative communication devices, special education, routine antiepileptic medications, orthopaedic care for scoliosis, hip dislocation and positional deformities of the feet, treatment for cardiac, renal, urologic and other medical issues and surgery for cryptorchidism if indicated.

History

The syndrome is named after Dutch geneticists David A. Koolen and Bert B. A. de Vries, who helped discover the syndrome in 2006.

References

References

1. Lupski JR. (2006). "Genome structural variation and sporadic disease traits.". Nat Genet.
2. (2009). "Phenotypic expansion and further characterisation of the 17q21.31 microdeletion syndrome.". J Med Genet.
3. (2006). "A 17q21.31 microdeletion encompassing the MAPT gene in a mentally impaired patient.". Cytogenet Genome Res.
4. (2008). "Evolutionary toggling of the MAPT 17q21.31 inversion region.". Nat Genet.
5. (August 26, 2015). "The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant". Springer Science and Business Media LLC.
6. (2006). "Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability.". Nat Genet.
7. (2007). "A 17q21.31 microduplication, reciprocal to the newly described 17q21.31 microdeletion, in a girl with severe psychomotor developmental delay and dysmorphic craniofacial features". Eur J Med Genet.
8. (2008). "Clinical and molecular delineation of the 17q21.31 microdeletion syndrome.". J Med Genet.
9. (September 2006). "Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome". Nat. Genet..
10. (2009). "17q21.31 microdeletion syndrome: further expanding the clinical phenotype.". Cytogenet Genome Res.
11. "Koolen de Vries syndrome {{!}} Genetic and Rare Diseases Information Center (GARD) – an NCATS Program".
12. (2006). "A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism.". Nat Genet.