Koolen‐de Vries syndrome in a 63‐year‐old woman: Report of the oldest patient and a review of the adult phenotype

Abstract Koolen‐de Vries syndrome (KdVS) is a rare genetic disorder caused by a de novo microdeletion in chromosomal region 17q21.31 encompassing KANSL1 or by a de novo intragenic pathogenic variant of KANSL1. KdVS is typically characterized by intellectual disability (ID), variable from mild to severe, developmental psychomotor delay, especially of expressive language development, friendly disposition, and multiple systemic abnormalities. So far, most of the individuals affected by KdVS are diagnosed in infancy or in adolescence; to the best of our knowledge, only 34 (including ours) adults have been reported in literature. Here we present the adult phenotype of a 63‐year‐old Italian woman affected by KdVS, caused by a 17q21.31 microdeletion. She is, to our knowledge, the oldest affected individual reported so far. We collected her clinical history and photographs, as well as those of other 26 adult patients described so far and compared her to them. We propose that the cardinal features of KdVS in adulthood are ID (ranging from mild to severe, usually moderate), friendly behavior, musculoskeletal abnormalities (especially scoliosis), and facial dysmorphism (a long face and a pronounced pear‐shape nose with bulbous overhanging nasal tip). Therefore, we suggest considering KdVS in differential diagnosis in adult patients characterized by these features.

phenotype correlation studies did not show important clinical differences between the two groups of patients (Koolen et al., 2016;Zollino et al., 2015). KANSL1 is a widely expressed gene and encodes the KAT8 regulatory NSL complex Subunit 1, which belongs to a complex involved in chromatin modification (Koolen, Dupont, et al., 2012).
The prevalence of KdVS was initially estimated as one in 16,000 individuals (Koolen et al., 2008). Following reports of deletions involving KANSL1 in a cohort of children with developmental delay and/or ID showed a frequency of 0.11% and a prevalence of 1 in 55,000 individuals (Koolen et al., 2016). The prevalence of the KANSL1 SNVs is still to be assessed, due to limited number of known patients, but preliminary data suggest that they might be as frequent as deletions (Koolen et al., 2016).
KdVS is typically characterized by developmental psychomotor delay, which especially involves expressive language development, and ID, which can vary from mild to severe. Neonatal hypotonia is a common characteristic of KdVS and may be associated with feeding difficulties and hospitalization during the first year of life. IUGR and low birth weight can occur but body weight often improves; short stature, if present, is proportionate (Koolen et al., 2016;Zollino et al., 2015). Epilepsy is reported in about 50% of patients, with typical childhood-onset focal seizures, multifocal epileptiform discharge EEG patterns and various structural brain abnormalities in MRIs (Myers et al., 2017). Individuals with KdVS are typically characterized by an amiable and friendly disposition comparable to Angelman and Williams Syndromes, with a strong memory for social-contextual information (Egger et al., 2013). Behavioral problems such as ADHD, ASD, anxiety, and stammering have also been reported (Koolen et al., 2016). Facial dysmorphism is typically reported in KdVS patients, including a long face, upward slanting palpebral fissures, narrow/short palpebral fissures, ptosis, epicanthal folds, tubular or pearshaped nose, bulbous nasal tip, everted lower lip, and large/prominent ears (Koolen et al., 2016). Adult individuals with KdVS have been described to have a longer face, with a broadening of the chin and a more pronounced tubular or pear-shaped nose (Koolen et al., 2008).
From a genetic standpoint, all cases reported so far are "de novo." Parental molecular analysis of the 17q21.31 region has demonstrated that in all patients with all 17q21.31 microdeletion, at least one parent is a carrier of the H2 haplotype, which is associated with a common 900-kb inversion polymorphism, present in $20% of the European population (Koolen et al., 2008). Therefore, this inversion is a necessary (but not sufficient) factor for the deletion to occur (Koolen et al., 2008). Being caused by a de novo event, the risk of recurrence for parents with a child with KdVS is low. However, the possibility of a parental germinal mosaicism (at least two families already reported) or of a parental balanced chromosomal rearrangement involving 17q21.31 must be taken into consideration (Koolen, Kramer, et al., 2012). So far, most of the individuals affected by KdVS have been diagnosed in infancy or in adolescence (Ciaccio et al., 2016;Koolen et al., 2016;Zollino et al., 2015). Also fetal cases have been reported (Sauvestre et al., 2017 (Ciaccio et al., 2016;Dubourg et al., 2011;Koolen et al., 2006Koolen et al., , 2008Koolen et al., , 2016Moreno-Igoa et al., 2015;Morgan et al., 2018;Myers et al., 2017;Nascimento et al., 2017;Shaw-Smith et al., 2006;Terrone et al., 2012;Zollino et al., 2015; lastly, while concepting this manuscript, Amenta et al., 2020 andPascolini et al., 2021). In particular, we decided to collect the clinical characteristics of 27 (13 males and 14 females) out of 34 adult patients, excluding the seven patients (Morgan et al., 2018;Myers et al., 2017) whose clinical description was more focused on epileptology and on speech development respectively, in order to delineate the adult phenotype of this rare disease, which seems to be mainly characterized by ID, friendly behavior, musculoskeletal abnormalities, and facial dysmorphism.

| Clinical evaluation
A 38-year-old secundigravida woman was admitted to our genetic counseling service for a prenatal genetic consultation in 2019 in order to define the recurrence risk of a moderate ID present in her then 61-year-old paternal aunt. We collected the aunt's personal and family history (with the help of her brother as her parents were dead) (Table 1, patient P1). Written informed consent for publication of both clinical data and photographs was obtained from the patient, with approval of her family.
The aunt was born post-term from an assisted delivery with forceps. At birth, she suffered perinatal distress and during the first year of life, she had growth and feeding difficulties, which required hospitalization. She presented a delay of psychomotor development: she reached autonomous ambulation at the age of 2 years and the acquisition of language was delayed and characterized by stammering, which is still present. She attended special school and learned to read, write, and tell time, but she did not develop abstract mathematical reasoning and thinking. As a child, she had a few episodes of febrile convulsions, but no epilepsy occurred during her life. She has exhibited asthma since childhood, treated with corticosteroid therapy. The age at T A B L E 1 Clinical and molecular findings of 27 adult patients affected by Koolen- P7 (Amenta et al., 2020) P8 (Amenta et al., 2020) P9 (Koolen et al., 2008;Shaw-Smith et al., 2006) Gender  P7 (Amenta et al., 2020) P8 (Amenta et al., 2020) P9 (Koolen et al., 2008;Shaw-Smith et al., 2006) Epicanthal folds À À n.a.    P9 (Koolen et al., 2008;Shaw-Smith et al., 2006) Renal/urogenital anomalies Vesicoureteral reflux À À À n.a.
n.a.    menarche was 14 years, then menses were regular. Standard karyotyping performed during adolescence was reported to be normal.
As an adult, ID is present and its degree is moderate. She has always been living with her family because she is not independent in her daily activities and she is now working for a special social cooperative. The behavioral phenotype is characterized by a friendly and sociable personality and her family reports a relatively strong memory for social-contextual information, in particular for people close to her, such as family and friends. She has good conversational abilities, however with stammering; she learned to read and write as well as tell time. Nonetheless, numeracy is very difficult for her: she has not learned yet the four main calculations, she is still not able to handle money and did not develop abstract mathematical reasoning and thinking. She loves music very much and she sings at both home and work; she also likes attending theater courses in the special social cooperative she works in. In adulthood, she suffered by conductive hearing loss since her 40s and bilateral cataract was detected in her 50s and she reached menopause at 52 years. She presents scoliosis and a minor body asymmetry, but no cardiac, renal/urogenital, or skin abnormalities have ever been detected.
To better characterize the phenotype, we collected her photographs from infancy to now ( Figure 1). As an infant (Figure 1a- broadening of the chin, a more pronounced pear-shaped nose with bulbous overhanging nasal tip and more evident large/prominent ears.

| Auxological evaluation
Most adult patients (15/24, 63%) present a short stature. In females, the height ranges from 143 cm (À3 SD, our patient) to 168 cm; in males it ranges from 156 to 175 cm. While height seems to be decreased, weight tends to be increased in adult subjects. When the BMI (body mass index) was available (n = 14), overweight (25-29.9 kg/m 2 ) or true obesity (≥ 30 kg/m 2 ) occurred in eight (53%) of 15, while only two patients had a BMI below normal.

| Neurological and behavioral features
Feeding problems and especially hypotonia were common problems during infancy (67% and 88%, respectively). As adults, ID is a constant feature and it is quite variable from mild to severe, but a moderate degree seems the most common (14/26, 54%). Seizure/EEG anomalies were present in the natural history of 62% of subjects, even if they seem to seizure-free in adulthood. Structural CNS (central nervous system) anomalies are not uncommon, involving 52% of the subjects; they are variable but mainly involving enlargement of ventricules and dysgenesis/agenesis of corpus callosum.
From a behavioral standpoint, almost all adult patients (85%) present the distinctive friendly and amiable disposition but also anxiety is common (55%). Some experience autism-like disorders, panic attacks, and depression. A difficulty to perform ADL (activity of daily living) is present in 48% of subjects.

| Dysmorphic features
As adults, the long face and the tubular/pear-shaped nose are almost invariably constant dysmorphic features (96%). Everted lower lip is present in 52% of patients. Eyes can be involved variably, with upslanting palpebral fissures (46%), ptosis (43%), and epicanthal folds (35%). Moreover, characteristic large/prominent ears may be present (42%); our patient presents a triangle-shaped helix of the right ear. A broad chin is described in some adults. By observing photographs taken at various ages, when available, it is possible to confirm a coarsening of the dysmorphism, as they age.
Other musculoskeletal abnormalities have been less frequently described: craniosinostosis, prognathism and malocclusion class III, contractures, dislocation of the hip, shortness of the III-IV toe of the left foot.

| Hearing and visual impairment
A hearing involvement is not rare in KdVS: in particular, 43% of the adult patients show hearing impairment, either conductive or sensorineural. Eye involvement seems to be less frequent, but it is not uncommon: strabismus, hypermetropia, and retinal impairment are described in 35%, 20%, and 14%, respectively. In addition, cataract was reported in three patients, of whom two after birth and one in adulthood.

| Cardiovascular and renal/urogenital defects
Heart defects can be present in adults, in particular valvular defects are described in 24% of subjects. Atrio-ventricular septal defects are in 20% of adults and, less commonly, also arterial ectasia/dilatation, especially of aortic bulb, have been described (three patients).
Regarding urogenital defects, cryptorchidism/macrorchidism is a typical feature, reported in the natural history of 75% of adult male patients. Renal involvement is less frequent (vescicoureteral reflux and hydronephrosis both in 9%).

| Ectodermal abnormalities
Anomalies involving skin, hair, and teeth are not uncommon. Multiple moles have been reported in seven (30%) of 23 adult patients, as well as hyper/hypopigmentation of the skin (6/23, 23%). Dry/skin eczema has been reported in five patients, oligodontia in five patients, and small teeth in two. A female young woman presents progressive alopecia from age 2 years.

| DISCUSSION
The patient presented here is one of the rare adult subjects affected by KdVS; in particular, she seems to be the oldest affected individual reported in literature to the best of our knowledge (P1 in Table 1) and this patient provides additional information to the natural history of this rare condition.
It is noteworthy that we were able to collect her photographs from infancy to now. As a child (Figure 1a-c), she presented upward slanting palpebral fissures, large/prominent ears and a pear-shaped nose. As she aged (Figure 1d-f), narrow palpebral fissures and droopy eyelids became more evident as well as a broadening of the chin and a pronounced pear-shaped nose with bulbous overhanging nasal tip, which are described in the adult subjects (Koolen et al., 2008). In addition to that, ears became progressively larger. What is more, she also shows small teeth, a triangle-shaped helix of the right ear, and an atypical shortness of the III-IV toe of the left foot. This elf-like feature together with her amiable behavior let us consider the Williams-Beuren Syndrome (WBS) in the differential diagnosis (Egger et al., 2013). As an adult, our patient, who did not receive any specific treatment related to her disease apart from logopedics, showed moderate ID, mild speech impairment, kyphosis, conductive hearing loss since her 40s, bilateral cataracts detected in her 50s, in absence of other serious complications.
The case series include 13 males (12 with a 17q21.31 microdeletion and 1 with a KANSL1 pathogenic variant) and 14 females (11 with a 17q21.31 microdeletion and 3 with a KANSL1 pathogenic variant) aged ≥18 years, with ages that range from 18 to 63 years old.
Few adult patients have been collected until now, because of the rarity of the disease and its relatively recent molecular definition: the aim of our review was to understand the natural history of this rare syndrome and to define its adult phenotype.
By observing their clinical data, some useful information about the adult phenotype of this rare syndrome can be deductable: first of all, most adults present short stature and a tendency to overweight/obesity, as suggested by (Amenta et al., 2020), even if in the majority of them, neonatal hypotonia and feeding difficulties in infancy were described. In particular, our patient, the oldest, has the shortest stature among them all (143 cm, À3 SD) and is overweight (BMI 29.3 kg/m 2 ).
Concerning the neurological and behavioral features, we suggest they represent the distinctive elements of the disease in adulthood.
Indeed, ID is a feature shared by all adult subjects, with a variable degree (usually moderate, 54% of adults) and it is typically accompanied by a specific behavioral pattern. Adults with KdVS show a typical friendly behavior, confirming this as a major sign both in children and in adults; it is interesting to point out that our patient has a strong memory for social information for people close to her, such as family and friends, characteristics that have been strongly reported to be present in KdVS (Egger et al., 2013). This over-friendly disposition is often accompanied by behavior abnormalities, including anxiety (which seems to be quite common) and other possible disorders (panic attack, depression, shyness, etc…). Another important aspect to underline is that autonomy in daily activities often lacks or it is limited, as well as language skills, which may be poor in some adults (Amenta et al., 2020;Morgan et al., 2018).
In addition, in the collected adult subjects, a history of seizures is described in 62% of cases, which is slightly more than what is known in literature (Myers et al., 2017). Interestingly, seizures tend to remission and to be absent in adulthood; therefore, a detailed personal history should be carefully recorded, to avoid missing details in childhood (Amenta et al., 2020). Our review shows that also structural CNS abnormalities are variably reported in 52% of adults, as expected from literature, and are universal (Myers et al., 2017) even if enlargement of ventricles and dysgenesis/agenesis of corpus callosum seem to be the most frequent MRI findings.
Regarding dysmorphic features, almost all adult patients collected share a long face and a pronounced pear-shaped nose with bulbous overhanging nasal tip (Koolen et al., 2008): according to us, these two elements together should evoke the suspect of KdVS both in childhood and in adulthood. Moreover, by observing photographs taken at various ages, it is possible to confirm a widening of the chin and a coarsening of the dysmorphism as they age (Koolen et al., 2008).
What is more, peculiar but not constant aspects of KdVS in adulthood are the presence of everted lower lip and large/prominent ears: when present, these features may represent a confounding factor because they may evoke, together with the friendly behavior, a diagnosis of Williams-Beuren syndrome in adulthood. This consideration does not apply to childhood when the facial gestalt of WBS is instead distinctive (Kruszka et al., 2018).
Concerning other body districts, this review suggests that the major congenital abnormalities present in adulthood are the musculoskeletal findings, which are quite common in adult patients with KdVS.
We detected, in particular, spine (kyphosis/scoliosis) and feet deformities and joint hypermobility (JHM) but many other defects have been reported. The spine deformities may justify the presence of short stature in adulthood while feet deformity may be an early sign of the disease. For example, we identified in our routine clinic activity a prenatal case of KdVS by array-CGH on DNA extracted from amniotic fluid in a male fetus that presented with bilateral clubfoot, a cardiac hyperechoic focus, a malformation of the urinary tract, and a high-risk screening test for trisomy 13 and 18.
Regarding other characteristics, data from male adult patients suggest a history of crypto/macrorchidism is often present and data from all patients show that hearing impairment, either conductive or sensorineural is not uncommon, involving about half of the subjects. It is also necessary to consider the presence of ocular, cardiovascular (especially involving valvules), and renal defects that seem to be variably present but not to be distinctive features of the disease.
Finally, it is noteworthy that ectodermal abnormalities may represent a peculiar additional aspect of the disease; therefore, anomalies involving skin, hair, and teeth (oligodontia included) should be fully investigated during clinical evaluation.
To sum up, from an overall analysis of literature concerning KdVS and adult subjects, it emerged that it is possible to discriminate the phenotype in the different stages of life. In particular, it seems that childhood is characterized by hypotonia and feeding difficulties in the majority of children and by epilepsy in about 50% (Koolen et al., 2008). With increasing age, we noticed a progressive stability of the clinical picture, characterized by moderate ID, non-evolution of the neurobehavioral disorders, recovery from epilepsy, and absence of major internal organ involvement (Amenta et al., 2020). As for facial dysmorphism, they are present since birth and they tend to remain stable over time, although in childhood there is a tendency to hypotonic face, with open mouth appearance and protruding tongue, while in adulthood there is a tendency to elongation of the face, broadening of the chin and to a more pronounced tubular/pear-shaped nose (Amenta et al., 2020;Koolen et al., 2008).
To conclude, we propose that the cardinal features of KdVS in adulthood are ID (ranging from mild to severe, but usually moderate), friendly behavior, musculoskeletal abnormalities (especially scoliosis, JHM and feet deformity), and facial dysmorphism (a long face and a pronounced pear-shaped nose with bulbous nasal tip). Therefore, we suggest considering KdVS in differential diagnosis in adult patients characterized by these features, by opting for firstly an array-CGH analysis to search for 17q21.31 microdeletion and, if negative, for a KANSL1 sequencing to detect heterozygous pathogenic variants.
As more and more young and adult individuals are identified, further studies are necessary to define the long-term prognosis of patients with KdVS and to what extent supporting treatments can improve their phenotype.