Paula and Bobby
Parents of Lillie
Koolen-de Vries syndrome (KDVS)
What is Koolen-de Vries syndrome (KDVS)?
Koolen-de Vries syndrome is a rare genetic condition believed to occur in 1 in every 55,000 people. It is a recently discovered condition, and was first identified in 2006.
Characteristic features of the syndrome include mild-moderate intellectual disability with developmental delay. Low muscle tone in childhood is also a defining symptom of the syndrome.
Individuals with the syndrome are often described as having a sociable, happy personality.
Chromosome 17q21.31 Deletion Syndrome; Microdeletion 17q21.31 Syndrome
What gene changes cause Koolen-de Vries syndrome (KDVS)?
The syndrome is caused by either a microdeletion of a small part of chromosome 17, or by a mutation of the KANSL1 gene.
The deletions or mutations that cause the syndrome are random and the majority of individuals are the first in their family with the syndrome.
Microdeletion inheritance occurs when there is a deletion of several genes on a chromosome. The specific chromosome on which the deletions occur will determine the syndrome they cause.
n some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation which occurs during the reproductive process.
What are the main symptoms of Koolen-de Vries syndrome (KDVS)?
Facial and physical characteristics include a pear-shaped nose, long face, broad forehead, droopy eyelids and very prominent ears.
Other health conditions may include epilepsy, estimated to be a major symptom in 50% of individuals diagnosed with the syndrome.
Heart defects, kidney disease and bone abnormalities are also recognized symptoms in some affected individuals.
Possible clinical traits/features:
Wide nasal bridge, Cataract, Bulbous nose, Abnormal cardiac septum morphology, Abnormal aortic valve morphology, Aortic dilatation, Arachnodactyly, Atrial septal defect, Aplasia/Hypoplasia of the corpus callosum, Bicuspid aortic valve, Blepharophimosis, Cleft palate, Hypopigmentation of hair, Underdeveloped nasal alae, Generalized hypotonia, Cognitive impairment, Global developmental delay, Ichthyosis, Hypotrophy of the small hand muscles, Delayed speech and language development, Hypothyroidism, Hypotelorism, Broad forehead, Prominent nasal bridge, Hip dysplasia, Hydronephrosis, High palate, High forehead, High, narrow palate, Nasal speech, Hypermetropia, Kyphosis, Short stature, Scoliosis, Spondylolisthesis, Vertebral fusion, Upslanted palpebral fissure, Strabismus, Anteverted ears, Broad chin, Ptosis, Microcephaly, Reduced number of teeth, Prominent metopic ridge, Wide intermamillary distance, Pyloric stenosis, Variable expressivity, Sporadic, Ventricular septal defect, Pulmonic stenosis, Contiguous gene sy
How does someone get tested for Koolen-de Vries syndrome (KDVS)?
The initial testing for Koolen-de Vries syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing. ed.
Medical information on Koolen-de Vries syndrome
Koolen-De Vries syndrome is characterized by intellectual disability, hypotonia, a friendly demeanor, and highly distinctive facial features, including a broad forehead, long face, upslanting palpebral fissures, epicanthal folds, and tubular nose with bulbous nasal tip. More variable features include cardiac or genitourinary anomalies and seizures. The syndrome is caused by mutations in the KANSL1 gene and deletions in the chromosome 17q21.31 region (Zollino et al., 2012, Koolen et al., 2012).
Varela et al., (2006) reported a patient with many features of Angelman syndrome, who had normal standard chromosome results but a de novo 1-Mb microdeletion at 17q21.31 using array CGH. Clinically, her developmental delay was somewhat less expressed than in classical Angelman syndrome. She did not have ataxia, and she had an ASD and VSD. She developed a scoliosis at an early age.
Three patients were reported by Koolen et al., (2006). Intellectual disability was moderate. All had severe hypotonia, which led to severe motor retardation. They had long hypotonic facies, with ptosis, blepharophimosis, large low-set ears, pear-shaped noses, a long columella and hypoplastic alae nasi. The chin was broad, and all had cheerful personalities.
An excellent report of 22 patients (Koolen et al., 2008) gives a definitive picture of the dysmorphic features. The children are delayed, hypotonic, have long faces with a tubular or pear-shaped nose with bulbous tip, and the behavior is friendly.
Eleven patients were reported by Tan et al., (2009). Aortic root dilatation, recurrent joint dislocations, persistent fetal finger pads, hip dysplasia and conductive hearing loss were additional features.
A further four patients were reported by Wright et al., (2011). Patients had skin hyperpigmentation, numerous nevi and coarse facial features. Wright et al., (2011) suggest this microdeletion should be in the differential diagnosis of CFC (see elsewhere). The patient reported by Digilio et al., (2013) had a generalized increase in skin pigmentation with patchy depigmentation. Vitiligo was a feature in two patients reported by Maley et al., (2015).
Interruption of the pituitary stalk and complete growth hormone deficiency can also occur (El Chehadeh-Djebbar et al., 2011).
Two sib pairs were reported by Koonen et al., (2012). A parent had low-grade mosaicism in both.
The patient reported by Dornelles-Wawruk et al., (2013) had in addition fusion of many vertebrae and anemia. The deleted area contained MAPT, CRHR1, KANSL1, SPPL2C and STH.
A partial duplication of both thumbs, which were also broad, was reported by Barone et al., (2015).
Zollino et al., (2015) reported on genotype-phenotype correlations in 27 patients with 17q21.31 deletions and five patients with KANSL1 point mutations. Macrocephaly was detected in 24% of patients with the deletion and in 60% of those with the point mutation. Congenital heart disease was found in 35% of patients with the deletion. Koolen et al., (2015) described a cohort of 45 individuals with KdVS, of whom 33 had a 17q21.31 microdeletion and 12 carried a single-nucleotide variant in KANSL1. No genotype-phenotype correlations were apparent. The facial features were similar between the 17q21.31 deletion group and the KANSL1 mutation group. The most prominent dysmorphic features included a long face, upslanting palpebral fissures, narrow/short palpebral fissures, ptosis, epicanthal folds, tubular- or pear-shaped nose with bulbous nasal tip, everted lower lip, large prominent ears, and a high and narrow palate. Hypermetropia was present in 38%, and strabismus was noted in 41%. Hearing impairment was detected in 25% of cases and was most frequently conductive.
Ectodermal abnormalities were present in 67% of cases (multiple nevi, depigmentosa, hyperkeratosis, eczema, keratosis pilaris, café-au-lait maculae, ichthyosis vulgaris, acne vulgaris, piezogenic papules, and hemangiomas). Dental problems included enamel hypoplasia, caries, absence of secondary elements, and small, widely spaced or conical teeth. Musculoskeletal anomalies were present in 77% of cases. Intrauterine growth retardation was recorded in 26% and postnatal growth retardation in 35% of the cases. Neonatal hypotonia was reported in 86% of all cases. It frequently resulted in feeding difficulties and nasogastric tube feeding in the neonatal period. Congenital heart anomalies were present in 39% of individuals. Renal and urogenital anomalies were present in 45%.
All individuals had developmental delay/intellectual disability (mild in 42%, moderate in 37% and severe in 22%). Expressive language development was particularly affected, compared with receptive language or motor skills. Eighty-nine percent of the individuals were described as sociable and had an amiable affect. Behavioral problems were observed in 57% of cases. Seizures were present in 49% of all cases and were well-controlled with antiepileptic medications. Structural anomalies of the central nervous system were present in 53% (corpus callosum hypoplasia/aplasia, enlarged ventricles, hydrocephalus, heterotopias, communicating hydrocephalus, periventricular white matter abnormalities, and partial pituitary stalk interruption syndrome).
Ciaccio et al., (2016) described an adult patient with a 546-kb deletion in 17q21.31. The patient had typical facial appearance with long face, inverse epicanthal folds, low-set ears with hypoplastic auricular lobe, tubular nose, and microretrognathia. Additional features included scoliosis with gibbus deformity, cubitus valgus, pes planus, bilateral arachno-clinodactyly of the toes, hallux valgus, pachydermodactyly, cutaneous xerosis of pretibial region and atrophic scars.
The authors reviewed the literature on adult patients with Koolen de Vries syndrome. All the individuals presented with global developmental delay. Good language skills were reached around the 4th year of life. Cognitive impairment varied from mild to severe. Strabismus was present in 5/10, hearing impairment in 4/10, scoliosis in 8/10, joint hypermobility in 6/10, and positional feet deformity in 6/10. Epilepsy was present in up to 50% of patients. MRI abnormalities included periventricular and perivascular matter enlargement, corpus callosum, hippocampal dysplasia, and thin pituitary stalk. Congenital heart defects included pulmonary stenosis, septal defects, bicuspid aortic valve and patent ductus arteriosus. Urological abnormalities were present in up to 82% patients; joint hypermobility has been described in 73%.
Keen et al., (2017) described a 10-year-eight-month-old female with Koolen-de Vries syndrome and a frameshift heterozygous mutation in the KANSL1 gene. Clinical characteristics included hypotonia, esotropia, hip dysplasia and multiple ear infections. The intelligence was low-average with intact verbal intelligence; she had perceptual deficits, developmental dyspraxia, and severe speech disorder. Brain MRI showed mild dilatation of the ventricles, mega cisterna magna, and small pineal cyst without mass effect. Dysmorphic features included midface hypoplasia, hypertelorism, sparse eyebrows, upward slanting palpebral fissures, tubular or pear-shaped nose with a bulbous nasal tip, long and prominent philtrum, everted lower lip, abnormal hair color and texture, anterior open bite with malocclusion, and small and widely spaced teeth.
* This information is courtesy of the L M D.
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