Journal Information
Vol. 86. Issue 3.
Pages 162-164 (01 March 2017)
Vol. 86. Issue 3.
Pages 162-164 (01 March 2017)
Scientific Letter
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Koolen de Vries syndrome: A challenge in clinical practice
Síndrome Koolen de Vries: un reto en la práctica clínica
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María Moreno Samos, Esther Eugenia Moreno Medinilla
Corresponding author
esthermoreno84@hotmail.com

Corresponding author.
, Jacinto Luis Martínez Antón, Antonio Urda Cardona
Sección de Neuropediatría, Servicio de Pediatría, Hospital Materno Infantil, Hospital Regional Universitario de Málaga, Málaga, Spain
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Tables (2)
Table 1. Case characteristics.
Table 2. Comparison of the most relevant characteristics found in the most recently published series and in our patients.
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Dear Editor:

Koolen-de Vries syndrome (KDVS, OMIM 610443) is a rare genetic disorder with an approximate prevalence of 1 per 16,000 live births, with no predominance of either sex. It is characterised by neonatal hypotonia, intellectual disability, dysmorphic features (high and broad forehead, long face, palpebral fissures with epicanthic folds, pear-shaped nose) that become attenuated over the years, and friendly behaviour. Central nervous system abnormalities are also found in 80% of cases, such as epilepsy (50%) and brain malformations (hydrocephalus and agenesis or dysgenesis of the corpus callosum), congenital heart defects (valvulopathies and septal defects) in 40–63% depending on the series, and urogenital anomalies (cryptorchidism, hypospadias, vesicoureteral reflux, hydronephrosis, etc.) in up to 70%.1

It was first described in 2006 as a recurrent microdeletion localised in chromosome 17q21.31, between 500 and 650kb in length, that comprises up to five genes: CRHR1, SPPL2C, MAPT, STH and KANSL1 (or KIAA1267), in addition to two putative genes, MGC57346 and C17orf69. In most cases, these are de novo mutations. Although the role of these genes in the pathogenesis of this disease remains unclear, recent studies have demonstrated that both KANSL1 haploinsufficiency or point mutations are sufficient to produce the disease.2–4 The most recently published case series (with 45 patients) described that while the phenotype is not significantly different based on whether there is a 17q21.31 microdeletion or a nonsense mutation of the KANSL1 gene, there is wide phenotypic variability between individuals.4 A previously described predisposing factor is the inversion of chromosome 17 in one of the parents, which, while necessary, is not sufficient to produce the microdeletion, as it is a very common polymorphism that is found in up to 20% of the European population.1 Only two cases of sibling recurrence have been reported in two independent families in which the mothers had a mosaicism for the chromosome 17 deletion, which could be a risk factor for recurrence, underscoring the importance of offering genetic counselling to parents of affected children.5

We present a series of four patients with KDVS (Table 1). All patients had some of the clinical features included in the 37 symptoms described by Koolen in the first published series; however, the diagnosis was made when expanded molecular testing was requested following an initial battery of diagnostic tests that were inconclusive. We present a table that summarises what we consider to be the most relevant clinical features described in the most recently published and broader series and those found in our patients (Table 2). Intellectual disability and facial dysmorphism are the most frequently observed features, as was the case in our patients, although potential comorbidities need to be ruled out. Contrary to what has been reported in the literature, none of our patients presented with nephrourologic abnormalities.

Table 1.

Case characteristics.

  Case 1  Case 2  Case 3  Case 4 
Presenting complaint  Language delay  Psychomotor delay  Epilepsy  Delayed postural control 
Phenotype  Dolichocephaly, long face, low-set prominent ears and bulbous nose  Hypertelorism, broad nasal root, long philtrum, low-set anteverted ears, broadly spaced nipples and mild pectus excavatum  Skull disproportionate to face, broad forehead and low-set ears  Long face, hypertelorism, epicanthic folds and low-set ears 
Language  Monosyllabic  Absent
No verbal language 
Language delay  Poor, with difficulty in verbal expression 
Intellectual disability  Yes  Yes  Yes  Yes 
Behaviour  Friendly, but with difficulty in communicating with peers  Sociable  Friendly
Hyperactivity 
Affable
Attention deficit 
Epilepsy  No  Yes  Yes  No 
Brain MRI  Hypogenesis of corpus callosum  Hypoplasia of posterior corpus callosum  Ventriculomegaly in the absence of hydrocephalus. Cortical and subcortical atrophy  Very mild cortical and subcortical atrophy 
Karyotype  Normal  Normal  Normal  Normal 
Fragile X  Normal  Normal  Normal  Normal 
Array CGH  1600kb microdeletion in the 17q21.31 band affecting up to 13 genes, including MAPT and KANSL1  Deletion of chromosome 17q21.31 (tested in a different facility)  621kb microdeletion in 17q21.31 affecting the CRHR1, IMPS, MAPT, STH and KANSL1 genes  695kb microdeletion in 17q21.31 affecting the C17of69, IMP5, MAPT, STH and KANSL1 genes 
Echocardiogram  Normal  Bicuspid aortic valve  Normal  Normal 
Renal ultrasound  Normal  Normal  Normal  Normal 
Other    Short statute    Father with inversion polymorphism 
Table 2.

Comparison of the most relevant characteristics found in the most recently published series and in our patients.

  Koolen, 2008 (%)
N=22 
Zollino, 2015 (%)
N=32 
Koolen, 2016 (%)
N=45 
Our series (%)
N=
Dysmorphic features
Long face  74  75  75  50 
Bulbous nose  82  93.7  88.3  50 
Prominent ears  59  –  32.6  75 
Everted lower lip  –  93.7  71.4 
Epicanthic fold  68  –  52.3  50 
Macrocephaly  –  40  14.3  25 
Neurologic features
Hypotonia  96  100  86.4  50 
Intellectual disability  –  90  100  100 
Motor delay  100  –  97.3  75 
Language delay    87  100  100 
Epilepsy  50  50  48.9  50 
CNS structural malformations  –  50  52.9  75 
Friendly/amiable behaviour  89  95  88.7  100 
Musculoskeletal anomalies  25  40  76.7  25 
Heart defects  27  35  38.6  25 
Renal/urogenital anomalies  32  22  45.2 
Short stature  18  37  35.3  25 

Genetic testing in all cases identified mutations in one of the five genes that cause the disease. We ought to highlight the size of the mutation in case 1, which exceeded sizes reported to date.

Recently, the first case has been published of KDVS diagnosed prenatally through the detection of bilateral ventriculomegaly in the pregnancy ultrasound examination performed at 33 weeks’ gestation, with confirmation of the microdeletion by means of array-based comparative genomic hybridisation in a sample obtained by amniocentesis.6 This reinforces the importance of detecting the syndrome early, as it not only allows its aetiological diagnosis, but also genetic counselling for the family. Furthermore, considering that this is a fundamentally monogenic disorder, it is likely that it can benefit from pharmacologic treatment targeting the genome or proteome in the future if research is conducted on this field.

In conclusion, KDVS is a rare disease that must be included in the differential diagnosis of patients with unexplained intellectual disability with or without associated dysmorphic features or malformations. Considering the wide clinical variability that has been observed, we believe that genetic hybridisation techniques must be included at the level of brain MRI in the diagnostic evaluation of these patients.

References
[1]
D.A. Koolen, A.J. Sharp, J.A. Hurst, H.V. Firth, S.J.L. Knight, A. Goldenberg, et al.
Clinical and molecular delineation of the 17q 21.31 microdeletion syndrome.
J Med Genet, 45 (2008), pp. 710-720
[2]
D.A. Koolen, J.M. Kramer, K. Neveling, W.M. Nillesen, H.L. Moore-Barton, F.V. Elmslie, et al.
Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome.
Nat Genet, 44 (2012), pp. 639-641
[3]
M. Zollino, G. Marangi, E. Ponzi, D. Orteschi, S. Ricciardi, S. Lattante, et al.
Intragenic KANSL1 and chromosome 17q21.31 delections: broadening the clinical spectrum and genotype–phenotype correlations in a large cohort of patients.
J Med Genet, 52 (2015), pp. 804-814
[4]
D.A. Koolen, R. Pfundt, K. Linda, G. Beunders, H.E. Veenstra-Knol, J.H. Conta, et al.
The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant.
Eur J Hum Genet, 24 (2016), pp. 652-659
[5]
D.A. Koolen, J. Dupont, N. de Leeuw, L.E. Vissers, S.P. van den Heuvel, A. Bradbury, et al.
Two families with sibling recurrence of the 17q21.31 microdeletion syndrome due to low-grade mosaicism.
Eur J Hum Genet, 20 (2012), pp. 729-733
[6]
M. Egloff, F. Encha-Razavi, C. Garel, M. Bonnière-Darcy, A.E. Millischer, J.M. Lapierre, et al.
17q21.31 microdeletion: brain anomalies leading to prenatal diagnosis.
Cytogenet Genome Res, 144 (2014), pp. 178-182

Please cite this article as: Moreno Samos M, Moreno Medinilla EE, Martínez Antón JL, Urda Cardona A. Síndrome Koolen de Vries: un reto en la práctica clínica. An Pediatr (Barc). 2017;86:162–164.

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