You are here
Home > Blog > Family Practice Medicine > Koolen-de Vries Case Study

Koolen-de Vries Case Study

Welcome to NewMedicalTerms, your ultimate guide to the explanations and definitions of the majority of medical terms you may see.

Feel free to use our complete database with charts, tables and examples.

Koolen-de Vries syndrome in a 63-year-old woman: a review of the adult phenotype

Koolen-de Vries syndrome (KdVS): An Introduction

Also known as the 17q21.31 microdeletion syndrome, Koolen-de Vries syndrome (KdVS) was first described in 2006 in individuals with intellectual disabilities and organ abnormalities. KdVS was initially described in association with recurrent microdeletion encompassing 5 genes – CRHR1, KANSL1, MAPT, SPPL2C, and STH – at the 17q21.31 locus. Later in 2012, it was also found that about 20% of the cases are caused by the KANSL1 truncating variant.  A recent case series of 45 patients reported that while the phenotype of KdVS 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 affected individuals.

In 2008, the estimated prevalence of KdVS was 1 in 16,000 individuals. A study by Vulto van Silfhout et al reported a frequency of 0.11% among children with unexplained ID. The authors estimated the prevalence of the 17q21.31 deletion at 1:55,000 individuals.

Clinical manifestations of this syndrome include intellectual disability (ID), hypotonia, developmental delay, and distinct facial traits (long face, upslanting palpebral fissures, sparse eyebrows, long and prominent nose with bulbous nasal tip, long philtrum, and everted lower lip). Epilepsy is noted in 50% of the affected individuals. Other component manifestations include short stature (35-40%), cardiac septal defects (30 -40%), and failure to thrive in infancy (35%). Behavior in most KdVS patients is described as friendly, amiable, and cooperative.

To date all KdVS cases result from a de novo event and most fall into two genetically distinct haplotypes: the H1 haplotype and the inverted H2 haplotype. The H2 haplotype is enriched in Europeans (~20%), and carriers are predisposed to the 17q21.31 microdeletion.  Though the risk of recurrence for parents with a child with KdVS is low,  the possibility of a parental germinal mosaicism or of a parental balanced chromosomal rearrangement involving 17q21.31 must be taken into consideration.

This report highlights the case of a KdVS affected 63-year old Italian woman who presented with moderate ID, friendly behavior, and scoliosis with a de novo 17q21.31 microdeletion.

Case Report

Clinical evaluation

In 2019, a 38-year-old secundigravida woman was admitted to the genetic counseling service for a prenatal genetic consultation to define the recurrence risk of a moderate ID present in her then 61-year-old paternal aunt. The aunt’s personal and family history were collected after obtaining informed consent from her family.

The aunt was born post-term from an assisted delivery and she suffered perinatal distress. She had growth and feeding difficulties in the first year of life. She also presented a delay in psychomotor development and still had stammering and learning difficulties in numeracy. She loves music, sings well, and likes attending theater courses in the special social cooperative she works in. Conductive hearing loss was detected in her 40s, bilateral cataract in her 50s and she reached menopause at 52 years. She presents scoliosis and a minor body asymmetry; she never had cardiac, renal/urogenital, or skin abnormalities.

Physical examination results include short stature (143 cm, <3rd percentile), span 144 cm, weight 60 kg (50th centile), macrocephaly (OCF 58 cm, >97th percentile), inner canthal distance 3.2 cm (mean), interpupillary distance 6.5 cm (97th centile), and outer canthal distance 9.8 cm (97th centile). Dysmorphic features observed were: narrow palpebral fissures, droopy eyelids, pear-shaped nose, bulbous overhanging nasal tip, broadening of the chin, large/prominent ears with a triangular-shaped-helix of the right ear, and shortness of the III-IV toe of the left foot.

Genetic analysis

Array-based Comparative Genomic Hybridization (aCGH) CytoGenomics analysis carried out on the aunt showed a microdeletion in the 17q21.31 region spanning about 504-kb.

Karyotype analysis from peripheral blood was conducted in the pregnant niece after the KdVS diagnosis in her aunt was established and the results were normal. A FISH (Fluorescent In Situ Hybridization) analysis was done to exclude the presence of a balanced chromosomal rearrangement involving 17q21.31. The pregnancy progressed uneventfully and she gave birth to a healthy female.

Review of Literature

PubMed was searched, noting the published studies involving adult patients with Koolen-de Vries syndrome. Potentially eligible titles and/or abstracts were identified using keywords “Koolen-de Vries syndrome,” “17q21.31 microdeletion,” and “KANSL1”.

Methods and subjects

A total of 34 adult patients with Koolen-de Vries syndrome (KdVS) who were 18-year old and above at the time of clinical description were screened for the study; of which 15 were males (14 with 17q21.31 microdeletion and 1 with KANSL1 pathogenic variant) and 19 were females including the 63-year woman (16 with 17q21.31 microdeletion and 3 with KANSL1 pathogenic variant).

The clinical description of 4 adult patients in Myers et al. and 3 in Morgan et al. (2018) was more focused on epileptology and speech development, respectively, hence were excluded in the review.

To define the adult phenotype of the syndrome and to compare the patient in this study to the adult patients in the literature, both photographs and clinical characteristics of the subjects were evaluated. After calculating the percentage of each feature, 27 subjects (13 males and 14 females aged 18 to 63 years were included in the study; of which 23 subjects presented a 17q21.31 microdeletion and 4 presented a heterozygous pathogenic KANSL1 variant.

The region on 17q21.31 contains a common inversion polymorphism of approximately 900 kb, which is enriched in the European population [138–140]. The carriers of the H2 ancestral haplotype are predisposed to having offspring with 17q21.31 microdeletion syndrome [139–141]. Haploinsufficiency of KANSL1 involved in histone acetylation within this region is known to be the key disease mechanism in the deletion phenotype [142,143].


Auxological evaluation

  • About 63% of patients presented a short stature. In females, the height range was 143 cm (−3 SD, our patient) to 168 cm; in males, it was from 156 to 175 cm.
  • There was a significant increase in terms of weight. Overweight (25–29.9 kg/m2) or true obesity (≥ 30 kg/m2) occurred in 8 out of 15 adult patients, while only two patients had a BMI below normal.

Neurological and behavioral features

  • Feeding problems (67%) and hypotonia (88%) were common in the subjects during infancy.
  • ID (mild to severe) was a constant feature, however, moderate ID was the most common in about 54% of the patients.
  • Seizure/EEG anomalies were common in the natural history of 62% of subjects, even if they seemed to be seizure-free in adulthood.
  • 52% of the subjects had structural central nervous system (CNS) anomalies, especially enlargement of ventricles and dysgenesis/agenesis of the corpus callosum.

From a behavioral standpoint, 85% of the adult subjects presented a distinctive friendly, and amiable disposition. Anxiety was common in 55% of the subjects. Autism-like disorders, panic attacks, and depression were also reported in some subjects. 48% of subjects had difficulty performing ADL (activity of daily living).

Dysmorphic features

  • Long face and the tubular/pear-shaped nose were common in 96% of the adult subjects.
  • Everted lower lip was seen in 52% of the subjects.
  • Eye involvement was variable; upslanting palpebral fissures (46%), ptosis (43%), and epicanthal folds (35%).
  • Characteristic large ears were present in 42%; the patient in this study presented a triangle-shaped helix of the right ear.
  • Some adults had a broad chin. By observing photographs taken at various ages, a coarsening of the dysmorphism was confirmed as they age.

Musculoskeletal anomalies

  • Spine abnormality, such as scoliosis/kyphosis is more common in adult patients with KdVS (83%).
  • Positional deformity of feet (48%) and joint hypermobility (41%) are the other typical features.
  • Arachnodactyly (30%), cubita/halluces/genua valga (30%), minor body asymmetry (29%), tracheo/larynghomalacia (17%), and pectus deformities (13%) are the less common anomalies observed.
  • Craniosynostosis, prognathism and malocclusion class III, contractures, dislocation of the hip, shortness of the III-IV toe of the left foot are also reported but less frequently.

Hearing and visual impairment

Hearing impairment (43%) in the adult patients mainly were either conductive or sensorineural. Clinical features involving the eye were also present: strabismus (35%), hypermetropia (20%), and retinal impairment (14%). Cataract was reported in three patients (two after birth and one in adulthood).

Cardiovascular and urogenital defects

Heart defects were reported in adult KdVS patients: Valvular defects (24%) and atrioventricular septal defects (20%). Less commonly, arterial ectasia/dilatation, especially of the aortic bulb, has also been described in three patients.

Renal and urogenital defects have previously been described. Cryptorchidism/macroorchidism was present in 75% of the male patients. Vesicoureteral reflux and hydronephrosis were also seen, but less frequently (both in 9%).

Ectodermal abnormalities

Ectodermal anomalies are not uncommon; multiple moles 7/23, 30%), hyper/hypopigmentation of the skin (6/23, 23%), eczema (5/23, 22%), oligodontia (5/23, 22%), and small teeth (2/23, 9%). A female young woman presented progressive alopecia from age 2 years.


The patient presented in this study is the oldest KdVS patient ever reported in the literature. The overall analysis indicates that the adult phenotype of KdVS can be discriminated at different stages of life. The natural history of the subjects showed hypotonia and feeding difficulties in their childhood. Epilepsy was noted in 50% of the affected individuals. With increasing age, clinical features such as moderate ID, non-evolution of the neurobehavioral disorders, and developmental delay became more evident. Facial dysmorphism changed with age. The subjects had hypotonia with an open mouth appearance in infancy. With increasing age, the face elongated, chin broadened and the nose took a more pronounced tubular or pear-shape.


In conclusion, KdVS is a rare disorder that must be included in the differential diagnosis of adult patients with ID with or without facial dysmorphism.

Considering the wide clinical variability that has been observed, genetic hybridization techniques must be included to confirm 17q21.31 microdeletion or KANSL1

Oncology Related Tools



Latest Research

Koolen-de Vries syndrome

Similar Articles

Leave a Reply