{"id":49782,"date":"2023-06-30T10:28:59","date_gmt":"2023-06-30T10:28:59","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=49782"},"modified":"2023-07-11T06:37:59","modified_gmt":"2023-07-11T06:37:59","slug":"neurodevelopmental-manifestations-and-birth-defects-in-prader-willi-syndrome-findings-from-a-study-in-western-ukraine","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol16no2\/neurodevelopmental-manifestations-and-birth-defects-in-prader-willi-syndrome-findings-from-a-study-in-western-ukraine\/","title":{"rendered":"Neurodevelopmental Manifestations and Birth Defects in Prader-Willi Syndrome: Findings from a Study in Western Ukraine"},"content":{"rendered":"\n

Introduction\n<\/strong><\/p>\n\n\n\n

Prader-Willi\nsyndrome (PWS) is the most common genetic obesity syndrome with associated\nneuroendocrine deficits, learning difficulties and behavioural and psychiatric\nproblems. Hormonal deficiencies and metabolic complications cause early\nphysiological and neurodevelopmental disorders. This genetic syndrome is caused by a lack of paternally derived\nimprinted material on chromosome 15q11\u2013q13 1<\/sup>.\n<\/a><\/p>\n\n\n\n

The frequency of PWS ranges from 1\/10,000 to 1\/30,000.\nThis syndrome is present in both women and men, in all ethnic groups and races\nof our planet 2<\/sup>. PWS is caused by the absence of paternally\nexpressed genes on chromosome 15q11\u201313. Most often, part of the\nfather\u2019s 15th chromosome is deleted in 70-75% of cases in children with PWS\nsyndrome. In the remaining 20-25% of cases, the patient has two copies of\nmaternal chromosome 15 from the mother and no paternal copy 1<\/sup>. Since\nparts of the maternal chromosome are disabled through imprinting, they do not\nhave working copies of certain genes 3<\/sup>. <\/p>\n\n\n\n

Many individuals with PWS also have co-occurring\npsychosis, autism spectrum disorders (ASDs), dysregulated sleep and eating and\nmood disorders. PWS\nis very often characterized by irritability, tantrums, compulsive behaviors,\nhyperphagia, growth hormone dysregulation. Patients\nwith PWS require attention because they have\na big problem with food-seeking behaviors, needs, compulsions and other neurodevelopmental disorders 4,5<\/sup>. <\/p>\n\n\n\n

Since there is no screening\nof newborns for this pathology in Ukraine, the clinical manifestations of this syndrome\nmay not be noticed by parents or doctors in the early stages of the disease. As\nPWS is\naccompanied by various birth defects, such children are seen by different\ndoctors. Most often, parents and doctors pay attention when a child has a\nspeech disorder over the age of 3.<\/p>\n\n\n\n

The aim of our study wastodescribe cases of Prader-Willi Syndrome in both sexes with mutations and different clinical neurodevelopmental manifestations. <\/p>\n\n\n\n

Materials and methods<\/strong><\/p>\n\n\n\n

We\nobserved 9 children (5 boys and 4\ngirls) with Prader-Willi\nsyndrome from Lviv and Ivano-Frankivsk regions (Western Ukraine) who\nwere diagnosed and followed-up at the Institute of Hereditary Pathology,\nNational Academy of Medical Sciences of Ukraine, Lviv, for 4 years (2019\u20132022) and\nunderwent molecular genetic testing. The ages of children ranged from 1\nmonth to 7 years, with the mean\nvalue amounting to 3,6 years. The final diagnosis of PWS was given to 8\nchildren aged 3-7 years. PWS was confirmed by a molecular genetic method at the\nage of 1 month only in one girl.<\/p>\n\n\n\n

Inclusion\ncriteria included children with sedentary\nlifestyle, muscle hypotonia, mental retardation. <\/p>\n\n\n\n

Exclusion\ncriteria encompassed patients with obesity and without neurodevelopmental\ndisorders, without molecular genetic confirmation of PWS.<\/p>\n\n\n\n

PWS was suspected in\n21 patients, thus the parents turned to a geneticist for consultation. Due to\nthe war started by the aggressor country Russia, 4 children were forced to\nleave Ukraine and emigrate abroad. The parents of 5 children went to defend\ntheir native land from the enemy, so the problem of establishing an accurate\ndiagnosis receded into the background. Three mothers refused to undergo\nmolecular genetic testing due to the stress experienced by their children after\nmissile attacks in other regions of Ukraine. Therefore, the group size is small\n(9 children with molecular genetic tests), and\nthe study only focuses on\nchildren from two regions in Western\nUkraine.<\/p>\n\n\n\n

The control\ngroup consisted of 30 practically healthy children (13 girls and 17 boys) aged\n2-5 without birth defects and neuropsychological disorders.<\/p>\n\n\n\n

During the study,\nwe have used the following:<\/p>\n\n\n\n

card for monitoring the child\u2019s behavior; it included data on gross motor skills and visual-motor coordination, balance, lateralization (main arm\/leg), response to hearing, manual skills, graphomotor skills, aggressive and auto-aggressive behavior, relationship with the therapist, imitation, concentration of attention, child\u2019s behavior during the visit.<\/p>\n\n\n\n

Checklist for Autism Spectrum Disorder (CASD) for autism assessment with high reliability and accuracy 7<\/sup>. We used CASD as a fast and reliable method for screening children\u2019s diagnosis to identify the level and degree of manifestation of neurodisorder in PWS. The Questionnaire for Autism Spectrum Disorders (CASD) included 30 symptom-questions that determined the child\u2019s behavior problems in 6 areas:<\/p>\n\n\n\n

Problems with social interaction;<\/p>\n\n\n\n

Obsessive actions (perseveration);<\/p>\n\n\n\n

Body-sensory (somatosensory) disorders;<\/p>\n\n\n\n

Deviation in communication and development;<\/p>\n\n\n\n

Mood disorder;<\/p>\n\n\n\n

Problems with attention and understanding of danger.<\/p>\n\n\n\n

A questionnaire for parents to assess the degree of development of all of the child\u2019s communicative personality qualities and interpersonal relationships, designed for expert assessment of the communicative personality qualities of children, as well as their relationships with the surrounding people.<\/p>\n\n\n\n

Cytogenetic and molecular-genetic analyses (FISH), DNA methylation.<\/p>\n\n\n\n

Since the\nCASD is one of the auxiliary tools in the diagnosis of a neurodisorder, all 9\nchildren with PWS were additionally\nconsulted by a psychologist and a psychiatrist. The findings of these\nspecialists during a more in-depth psychodiagnostic examination confirmed the\nkey symptoms of the neurodisorder and the specifics of their manifestation.<\/p>\n\n\n\n

The obtained\ndata were standardized according to the Tenth Revision of the International\nClassification of Diseases (ICD – 10) and processed using the variational\nstatistics method, the “Statistica 5” program package, and Microsoft\nExcel – 2000: the study considered the arithmetic mean value (M), deviations\nfrom the arithmetic mean value (m), the value of statistical significance (p)\n6<\/sup>.<\/p>\n\n\n\n

Clinical manifestations and molecular results were collected from the\nmedical records of the patients. All study personnel data were anonymized prior\nto the analysis.<\/p>\n\n\n\n

Informed written consent was obtained from the parents of all\nparticipants. The\npresent research was conducted following the Declaration of Helsinki principles\nand approved by the Bioethics Committee of SI\n\u00abInstitute of Hereditary Pathology, National Academy of Medical Sciences of\nUkraine\u00bb, Lviv, Ukraine, \u2116 71, 02.03.2023.<\/p>\n\n\n\n

Result<\/strong>s <\/strong><\/strong><\/p>\n\n\n\n

The socio-economic status of the families was\nof average wealth and did not affect the access and availability of medical\nservices until February 2022. All plans were interrupted by the war with\nRussia, which insidiously attacked our land, began bombing peaceful towns and\nvillages, destroyed power plants in order to isolate Ukrainians from normal\nliving conditions.<\/p>\n\n\n\n

Parents consulted\na geneticist because they saw that their child was lagging behind peers for\nvarious reasons (Table\n1). Among the 9 children, 5 had developmental delays up to\none year, which their parents noticed, such as\nproblems with swallowing (1 boy and 1 girl), sedentary child (1 boy and 1 girl),\nobesity (1 boy and 1 girl). Although only the parents of 2 children complained\nof excess weight, obesity was diagnosed in 6 children during the\nendocrinologist\u2019s consultation. At the age of 3.5, the bone X-ray of patient K.\n(case 3 – 46 \u0425\u0425, upd(15)mat) corresponds to\nthe child’\u2019s age of 1 year and 9 months. At the same time, the X-ray of the\nhands of patient A. (case 2 – 46 \u0425Y, ish del (15)(q11-13)(D15S10-, D15Z1+,\nPML+) aged 9, exceeded the age norm and corresponded to a 12-year-old child.<\/p>\n\n\n\n

In the maternity hospital, birth defects due to ICD-10-CM were diagnosed in 4 boys and 1 girl with PWS: cryptorchidism (Q.53) in 3 cases, congenital shortening of upper limb, bilateral (Q.71.81) and other congenital malformations of vulva (Q52.7). In addition to cryptorchidism, one boy was also diagnosed with congenital malformations and deformations of the musculoskeletal system, namely congenital dislocation of left hip (Q.65.0) and right congenital torticollis (Q.68.01). Birth defects of the heart were diagnosed in two children under 1 year of age. The girl (case 8 -46, XX, del (15) (q11.2-12.2)) was diagnosed with an atrial septal defect (Q.21.1), the boy (case 7 -46 \u0425Y, del (15) (q11.2-13)) was diagnosed with a ventricular septal defect (Q.21.0) along with a previously diagnosed birth defect.<\/p>\n\n\n\n

In our study,\nPWS had a multifaceted and complex clinical appearance. Usually, problems with swallowing arose in the first days after the birth\nof a child. One boy even had a feeding tube used because the child was\nsedentary and had muscle hypotonia. Muscular system pathology was most often\nobserved in children, it was present in 7 (77.8%) cases: muscular hypotonia, hip\ndysplasia, scoliosis; while damage to the gastrointestinal tract was the least\nobserved, it was present in 2 (22.2%) girls: chronic constipation (case 5 – 46 \u0425\u0425, ish del (15)\n(q11-13) (SNRPN)) and hepatomegaly (case 3 – 46 \u0425\u0425, upd(15)mat). Hyperphagia is a pervasive problem affecting individuals\nwith PWS that increases with age. Disturbances from the endocrine (goiter\nand\/or obesity) and ophthalmological systems (most often strabismus) were found\nin 5 (55.6%) children.<\/p>\n\n\n\n

According to the statistical data,\nthe average age of mothers at the birth of their first child in Ukraine is 26.2\nyears 8<\/sup>. In our study, the age of mothers who gave birth to a child\nwith PWS ranged from 22 to 36\nyears (Table 2), and the average\nwas 25.1\u00b14.4 years of age. No\nstatistical difference was found regarding the age of the mothers of the\ncontrol group \u2013 24.9\u00b15.1 (\u0440>0.05).\nThe mother D. gave birth to a healthy son from her first pregnancy, and from\nher second pregnancy, at the age of 22, a boy with PWS (case 4 – 46, XY.ish del(15)( q11-13)(D15Z1+, D15S10-, PML+).<\/p>\n\n\n\n

Studying the reproductive anamnesis\nof the mothers, it was established that it was the first pregnancy for 5 (55.6%)\nwomen. It was the second\npregnancy for two women, and a healthy child was born from the first one. In a\n36-year-old woman, it was the 4th pregnancy, where the girl was diagnosed with PWS at 1 month. Healthy children were born from the\nprevious three pregnancies from another husband.<\/p>\n\n\n\n

Among the 9 surveyed families and the\ncontrol group, there were no consanguineous marriages. Only in 1 (11.1%) case was there a delay in\nmental and physical development in the cousin on the mother\u2019s line. In the\nremaining 8 families, such pathology was absent. 6 (66.7%) women had contractions during\npregnancy. Most often, women noticed the inactivity of the fetus. In 3 (33.3%)\nwomen, the pregnancy was uneventful. At ultrasound during pregnancy, only two women had no obvious pathology\nof the fetus and placenta. Higher nuchal\ntranslucency measurement, sedentary\nfetus, in combination with fetal intrauterine development delay was observed in\n3 (33.3%) cases.<\/p>\n\n\n\n

In 4 (44.4%) cases, the pregnancies\nended with cesarean section. The weight of the fetus varied from 2800 to 3700 g (average weight \u2013\n3212.2\u00b1295.5 g). The height of children who were subsequently diagnosed with PWS ranged from 48 to 53 cm, with the average value\nequaling 50.4\u00b11.5 cm. No statistical difference (\u0440>0.05) was found regarding\nthe weight (3180.4\u00b1321.7 g) and height (50.1\u00b12.2 cm) of the children in control\ngroup in comparison with patients with PWS. A cesarean section was performed on a pregnant\nwoman with preeclampsia, the child was born weighing 2800 g (case 1). Only at\nthe age of 5, due to molecular genetic testing, the boy was diagnosed with PWS (case 6 – 46 \u0425Y, arr 15q11.2).<\/p>\n\n\n\n

According to\nthe questionnaire for parents, the main complaints of the parents were\nhyperphagia and problem behavior, which contributed to the deterioration of the\nwell-being and quality of life of both the child and relatives. Parents of children with PWS\nemphasized the fact that they must constantly take care of the child, pay\nattention to its nutrition and changes in mood and behavior.<\/p>\n\n\n\n

In our group the neurodevelopmental disordersand pathogenic gene spectrum between patients were different (Table 3). Only in one case, in a newborn, a 1-month-old girl (case 1) with muscular hypotonia and sedentary behavior was diagnosed with PWS using molecular genetic testing \u2013 46, XX, rsa 15q11.2(P245)x1.<\/p>\n\n\n\n

Specialists suspected the diagnosis of\nautism in several children (cases 2, 4, 5), therefore, along with other\nmethods, a Questionnaire on Checklist for Autism Spectrum Disorder (CASD) was used. It should be noted that impaired\nneurodevelopment of a child can be one of the causes of syndromic autism. Each Questionnaire on CASD was\nscored 1 point in the presence of certain developmental abnormalities, while\nnormal development of the child was defined as 0 points (Table 3). The procedure\nfor examination of children with PWS was carried out individually. The duration\nof a one-time meeting was determined by the individual needs and capabilities\nof the child and lasted 30-50 minutes on average.<\/p>\n\n\n\n

The total number of points according to\nthe results of the survey for children with PWS determined the risk of\nthe autistic spectrum disorder at 15 points. Accordingly, a higher number of\npoints (> 15) scored on this survey corresponded to a moderate and severe\ndegree of autism. Therefore, 3 of the examined children with PWS are at risk and need\nfurther monitoring, while 5 children scored 18-20 points, which indicates the\npresence of autism spectrum and requires in-depth diagnosis and long-term\ntreatment. In our study, this test was not performed in 1 girl (case 1 – 46,\nXX, rsa 15q11.2(P245)x1), as the diagnosis was made at the age of 1 month. The oldest among the children who were tested\nwas a 7-year-old boy (case 9 -46\n\u0425Y, ish del (15) (q11.2-12)), who scored 14 points.<\/p>\n\n\n\n

Children with PWS have problems with\nsocial interaction \u2013 most of the children observe play with peers, but do not\ninteract with them. In 5 children (cases 2, 4, 5, 6, 7) with this syndrome, limited interpersonal\ninteraction was found, 3 children (cases 5, 6, 7) needed additional motivations\nto establish visual contact, and 2 boys (cases 2, 4) did not look into the eyes\nof the interlocutor at all (Table 3). Egocentrism was clearly traced in two\nchildren (cases 2, 4) \u2013 they did not pay attention to the presence of others\nand understood the manifestations of social interaction poorly. <\/p>\n\n\n\n

Stereotypical and repetitive play as a\nmanifestation of the disorder was observed in 3 boys with PWS (cases 2, 4, 7).\nParents also noted that these children often had unusual repetitive movements,\nsuch as clapping the palms in excitement. Among the somatosensory\ndisorders, atypical craving for twisting and rocking were noted in two boys\n(cases 2, 4). In our study 3 girls and 2\nboys (cases 3, 4, 5, 6, 8, 9) had problems with nutrition, in particular the\ninability to chew hard and large pieces, and to keep food in the mouth for a\nlong time without swallowing it. Only 2 girls and 1 boy (cases 3, 8, 9) did not\nshow hypersensitivity to certain sounds. Parents observed sleep disorders in 3\nchildren (cases 5, 6, 7). <\/p>\n\n\n\n

All children experienced atypical\ncommunication and development, which were manifested by varying degrees of deceleration\nof language development and limitation of spoken speech. 3 children (cases 5,\n6, 7) had mood swings and hyperactivity. Emotional lability was inherent in 3\nboys (cases 2, 4, 7). There were no difficulties with the expression and\nrecognition of emotions in 2 girls and 1 boy (cases 3, 8, 9). The ability to\nfocus excessively on a particular activity or object was observed in 3 children\n(cases 7, 8, 9), the other 5 children had problems with attention and personal\nsafety. Impulsiveness was inherent in 2 girls and 3 boys (cases 2-6), 2 boys\nand 1 girl (cases 7, 8, 9) were fussy. <\/p>\n\n\n\n

Most often, neurodevelopmental disorders with the\ncondition of children assessed at 20 points, were observed in boys aged 3 (case\n4 -46, XY.ish del(15)( q11-13)(D15Z1+, D15S10-, PML+)) and 4 (case 2 -46 \u0425Y,\nish del (15)(q11-13)(D15S10-, D15Z1+, PML+)).<\/p>\n\n\n\n

In our study, different genotypes seemed\nto account for the difference in phenotype in PWS patients. We found a delay in\ntime of the diagnosis in these patients, although the majority of children had\nneonatal hypotonia and other suggestive phenotypic features, again emphasizing\nthe need for increased awareness of this syndrome as well as genetic\ncounseling.<\/p>\n\n\n\n

In children with PWS, the course of the pathology may be accompanied by symptoms from other organs and systems (digestive, skin, ophthalmic, skeletal-muscular, endocrine, cardiac and hepatobiliary systems), which are often left out attention of clinicians. According to the data of the individual development program of the child with PWS, specialists selected appropriate rehabilitation measures that focused on the development of the emotional and volitional sphere, sensory, motor and language activities. 3 months after the classes, 5 (55.6%) parents noticed an improvement in the child\u2019s condition. In 2 (22.2%) children, the slow progress of social skills and the development of the emotional and volitional sphere were noted. However, in 2 (22.2%) children who previously worked with specialists, regression was observed due to frequent anxiety attacks caused by the war in Ukraine, which occurred 3-4 times a day and lasted up to 1.5-3 hours. Children and parents experienced post-traumatic stress disorder. After the children were diagnosed with PWS, they were referred to specialists of various profiles (ophthalmologist, neurologist, endocrinologist, psychologist) and received treatment as needed. Appropriate treatment for various manifestations of PWS was prescribed by doctors of various profiles, in particular, 2 patients were prescribed somatotropic hormone.<\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Table 1<\/strong>: Clinical manifestations of Prader-Willi syndrome in children<\/strong>.<\/p>\n

<\/p>\n

Click here to view Table<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Table 2: Peculiarities of the reproductive history of mothers of children with Prader-Willi syndrome<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Case<\/strong><\/p>\n<\/td>\n

\n

Reproductive Anamnesis<\/strong><\/p>\n<\/td>\n

\n

Family History<\/strong><\/p>\n<\/td>\n

\n

Pregnancy<\/strong><\/p>\n<\/td>\n

\n

USG during Pregnancy<\/strong><\/p>\n<\/td>\n

\n

Mother’s age at delivery<\/strong><\/p>\n<\/td>\n

\n

Delivery<\/strong><\/p>\n<\/td>\n

\n

Weight, g<\/strong><\/p>\n<\/td>\n

\n

Hight, cm<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

1<\/p>\n

\n<\/p>

\n<\/p><\/td>\n

\n

3 pregnancies – three healthy children from another man<\/p>\n<\/td>\n

\n

no<\/p>\n<\/td>\n

\n

reduced fetal movements<\/p>\n<\/td>\n

\n

delay in intrauterine development of the fetus<\/p>\n<\/td>\n

\n

36<\/p>\n<\/td>\n

\n

breech birth<\/p>\n<\/td>\n

\n

2800<\/p>\n<\/td>\n

\n

52<\/p>\n<\/td>\n<\/tr>\n

\n

2<\/p>\n<\/td>\n

\n

–<\/p>\n<\/td>\n

\n

yes<\/p>\n<\/td>\n

\n

anemia, grade II, chronic tonsylit, chronic cholecystitis<\/p>\n<\/td>\n

\n

higher measurement of nuchal translucency, reduced fetal movements, delay in intrauterine development of the fetus<\/p>\n<\/td>\n

\n

22<\/p>\n<\/td>\n

\n

caesarean section<\/p>\n<\/td>\n

\n

3460<\/p>\n<\/td>\n

\n

51<\/p>\n<\/td>\n<\/tr>\n

\n

3<\/p>\n<\/td>\n

\n

–<\/p>\n<\/td>\n

\n

no<\/p>\n<\/td>\n

\n

reduced fetal movements<\/p>\n<\/td>\n

\n

delay in intrauterine development of the fetus<\/p>\n<\/td>\n

\n

25<\/p>\n<\/td>\n

\n

breech birth<\/p>\n<\/td>\n

\n

3400<\/p>\n<\/td>\n

\n

49<\/p>\n<\/td>\n<\/tr>\n

\n

4<\/p>\n<\/td>\n

\n

1 healthy son<\/p>\n<\/td>\n

\n

no<\/p>\n<\/td>\n

\n

normal<\/p>\n<\/td>\n

\n

higher measurement of nuchal translucency, reduced fetal movements,  delay in intrauterine development of the fetus<\/p>\n<\/td>\n

\n

22<\/p>\n<\/td>\n

\n

normal<\/p>\n<\/td>\n

\n

3400<\/p>\n<\/td>\n

\n

51<\/p>\n<\/td>\n<\/tr>\n

\n

5<\/p>\n<\/td>\n

\n

1 miscarriage<\/p>\n<\/td>\n

\n

no<\/p>\n<\/td>\n

\n

gestosis<\/p>\n<\/td>\n

\n

higher measurement of nuchal translucency, reduced fetal movements,  delay in intrauterine development of the fetus<\/p>\n<\/td>\n

\n

23<\/p>\n<\/td>\n

\n

caesarean section<\/p>\n<\/td>\n

\n

3000<\/p>\n<\/td>\n

\n

48<\/p>\n<\/td>\n<\/tr>\n

\n

6<\/p>\n<\/td>\n

\n

–<\/p>\n<\/td>\n

\n

no<\/p>\n<\/td>\n

\n

anemia grade I, gestosis<\/p>\n<\/td>\n

\n

reduced fetal movements<\/p>\n<\/td>\n

\n

24<\/p>\n<\/td>\n

\n

caesarean section<\/p>\n<\/td>\n

\n

2950<\/p>\n<\/td>\n

\n

50<\/p>\n<\/td>\n<\/tr>\n

\n

7<\/p>\n<\/td>\n

\n

1 healthy daughter<\/p>\n<\/td>\n

\n

no<\/p>\n<\/td>\n

\n

normal<\/p>\n<\/td>\n

\n

normal<\/p>\n<\/td>\n

\n

27<\/p>\n<\/td>\n

\n

normal<\/p>\n<\/td>\n

\n

3200<\/p>\n<\/td>\n

\n

50<\/p>\n<\/td>\n<\/tr>\n

\n

8<\/p>\n<\/td>\n

\n

–<\/p>\n<\/td>\n

\n

no<\/p>\n<\/td>\n

\n

normal<\/p>\n<\/td>\n

\n

normal<\/p>\n<\/td>\n

\n

24<\/p>\n<\/td>\n

\n

caesarean section<\/p>\n<\/td>\n

\n

3700<\/p>\n<\/td>\n

\n

53<\/p>\n<\/td>\n<\/tr>\n

\n

9<\/p>\n<\/td>\n

\n

–<\/p>\n<\/td>\n

\n

no<\/p>\n<\/td>\n

\n

reduced fetal movements<\/p>\n<\/td>\n

\n

reduced fetal movements<\/p>\n<\/td>\n

\n

23<\/p>\n<\/td>\n

\n

normal<\/p>\n<\/td>\n

\n

3000<\/p>\n<\/td>\n

\n

50<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n
\"\"<\/td>\n\n

Table 3: Checklist for Autism Spectrum Disorder (CASD) Results According to Detected Mutations<\/strong><\/p>\n

<\/p>\n

Click here to view Table<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Discussion<\/strong><\/p>\n\n\n\n

PWS is a multi-system\ngenetic disorder caused by chromosomal changes in segment 15q11-q13,<\/em>\nindividuals with this syndrome usually present in neonatal period with poor\nsucking with hypotonia, developmental\ndelay, mental, behavioral symptoms and a specific physical phenotype. In\nour study, we reported the results of the genetic analysis, clinical features\nand neurodevelopmental disorders in children with PWS that match the data 9<\/sup>. <\/strong>Typical PWS manifestations in our 9 infants included\nhypotonia \u2013 5 (55.6%), absence of sucking and swallowing reflexes \u2013 2(22.2%), breech birth \u2013 2(22.2%)\nand reduced fetal movements \u2013 5(55.6%). Mothers of\nchildren with PWS with hypotonia noted that they had\ndifficulty in feeding the babies immediately after birth. After examination by\ndoctors, feeding tube was used in 2 cases.<\/p>\n\n\n\n

In our study, at ultrasound\nduring pregnancy, we observed certain clinical features of the fetus,\nincluding fetal intrauterine development delay \u2013 5\n(55.5%) and higher nuchal translucency measurement \u2013 3 (33.3%). Our study indicates that the\npathology was not detected in 2 (22.2%)\npregnant women during the ultrasound examination.<\/p>\n\n\n\n

Similar to our subject, experts note that reduced\nfetal movements, malpresentation of the fetus, severe intrauterine growth restriction\ninclude the prenatal sonographic phenotype of PWS. Since these findings are not\nspecific for PWS, however, the combination of some of them (especially severe\nintrauterine growth retardation and polyhydramnios) may prompt clinicians to\nperform invasive testing leading to prenatal molecular cytogenomic diagnosis 10<\/sup>. <\/p>\n\n\n\n

According to Italian doctors 11<\/sup> <\/strong>newborns with PWS in\n1988-2018 showed a lower average birth weight by 1\/2 kg and a shorter average\nbirth height by 1 cm than healthy newborns. In contrast, in our study, only 1\ngirl was born with a weight of 2800 g, all other children weighed more than\n3000 g. Another girl, who was born\nby caesarean section, was 48 cm of height and weighed 3000 g, which met the\nneonatal anthropometric standards.<\/p>\n\n\n\n

Argentinian physicians indicate that 22% patients with PWS had birth defects, with a risk 5.4 to 18.7 times higher than the general\npopulation 12<\/sup>. Doctors from the Netherlands indicate the\npresence of cryptorchism in 95.9% of boys 13<\/sup>. Our study\nrevealed that 6 (66.7%) out of 9 children with PWS, had birth defects: 5\nmalformations were diagnosed in the maternity hospital, and 1 other child had a\nheart defect diagnosed during the year of observation.<\/p>\n\n\n\n

Our data are\nconsistent with the study by scientists who report that hypotonia, hypophagia,\nand abnormal genital development are common characteristics of neonates with\nPWS in the Chinese population 14<\/sup>. In our study, after the\nbirth of the child, the mother observed inactivity, lethargy, lack of sucking\nreflex, so the doctors suspected PWS (case 1). Since\nthe clinical signs were strongly suggestive of PWS, the mother was strongly\nrecommended to do molecular genetic testing of her daughter. As parents point\nout, they are most concerned about hyperphagia and obesity in children with\nPWS, as well as difficulties with sleep, as it violates\nthe family life.\nIn addition, such children have problem with visual-spatial functions. In our group, the main clinical characteristics were\nrepresented by short stature, obesity, muscular hypotonia, developmental delay, cognitive disability and behavioral\ndiseases.<\/p>\n\n\n\n

As doctors note, the diagnosis is not\nalways possible to make in time, and 14.3% of patients were diagnosed with PWS at the age of 4-10 years 9<\/sup>. In our study, 5\n(55.5%) children aged 4-7 years were given this diagnosis.<\/p>\n\n\n\n

A high degree of variability in clinical severity is observed within PWS,\nacross clinical features such as language and motor function. Our observations\nregarding clinical manifestations coincide with the data of doctors, who note\nthat PWS is accompanied by neuroendocrine disorders, as well as behavioral and\npsychiatric problems 5,15<\/sup>. <\/p>\n\n\n\n

This study also illustrates the potential importance of early diagnosis and\ncareful detection of ophthalmic pathology, since 5 (55,5%) children were\ndiagnosed with strabismus,\nastigmatism and swelling of the optic nerve discs of both eyes. Our data are consistent with the Global PWS Registry\n(USA), where the prevalence of strabismus, amblyopia, and hyperopia are\nconsiderably higher in the PWS population represented 16<\/sup>. <\/p>\n\n\n\n

Scientists from the Netherlands note\nthat 17% of patients with ASD have hypothyroidism 17<\/sup>. In contrast,\nin our group of 9 children, 4 (44.4%) were diagnosed with goiter. Perhaps this\nis due to the fact that the Lviv and Ivano-Frankivsk regions belong to the\ngoitre endemic zone.<\/p>\n\n\n\n

Sleep disturbances in children with PWS are indicated by many\nauthors 18,19<\/sup>, in particular, in our group, the parents of 3\nchildren drew attention to this symptom.<\/p>\n\n\n\n

Maladaptive behaviors among 9 children with\nPrader-Willi syndrome were assessed using the Checklist for Autism Spectrum\nDisorder. Studying the psychological characteristics of patients in our group,\nit was established that 5 children were included in the autism risk group\naccording to the Checklist for Autism Spectrum Disorder. Patient \u0421. (case 3)\nwith mutation 46XX,upd(15)mat, which was detected by DNA methylation, was found to have a low\nlevel of probability of autism. There are observations that indicate the\npositive role of training game exercises when children with PWS were involved\nin them 20<\/sup>. <\/p>\n\n\n\n

Patients with different mutations were\ndiagnosed with different levels of neurodevelopmental disorders 4<\/sup>.\nAt that time, many articles described the presence of aggressive behavior in\nchildren 6,21<\/sup>, but in our study, parents had no complaints about this.<\/p>\n\n\n\n

Among 9 children there were no seizures,\nalthough they were examined by doctors, which is supported by the data of\nresearchers who did not find a reliable difference between epileptic seizures\nand this genetic syndrome 22<\/sup>. <\/p>\n\n\n\n

Our observations are consistent with other\nauthors who point to repetitive interests and behaviors of such children. This\nis especially noticeable at the doctor\u2019s appointment, when the child sees a\npicture on the wall in the office and asks something dozens of times. Since PWS\nis a neurodevelopmental disorder associated with social cognitive challenges,\nthe behavior of children with PWS has a significant and dramatic impact on the\ndaily functioning and quality of life of the patient and their families. After\na period of impaired social sensitivity, they develop behavioral problems such\nas temper tantrums, stubbornness, and excessive foraging. According\nto the observations of Australian doctors on 50 patients with PWS, such persons require intensive supervision by relatives,\nwhich can negatively affect the quality of life of all family members 19<\/sup>. <\/p>\n\n\n\n

Our study revealed that 6 (66.7%)\nout of 9 children with PWS had birth defects: 5 malformations were diagnosed in\nthe maternity hospital, and 1 other child had a heart defect diagnosed during\nthe year of observation.<\/p>\n\n\n\n

At ultrasound during pregnancy, we\nobserved certain clinical features of the fetus, including fetal intrauterine development delay \u2013 5 (55.5%)\nand higher nuchal translucency measurement \u2013 3 (33.3%).<\/p>\n\n\n\n

According to the checklist of autism spectrum\ndisorders (CASD), 3(33.3%)\nof the examined children with autism syndrome are at risk and require further\nmonitoring, and 5(55.5%) children scored 18-20 points, which indicates the\npresence of an autistic range and requires in-depth monitoring during diagnosis.\n<\/p>\n\n\n\n

A multisystem approach should\nbe applied to families with a child with PWS, which includes consultation with\ndoctors of various specialties, such as neurologists, genetics, endocrinologists,\npsychologists, ophthalmologists, nutritionists, etc.<\/p>\n\n\n\n

At the moment the issue of\nimproving the algorithm for early diagnosis of impaired neurodevelopment in\nchildren caused by genetic and hereditary diseases remains unresolved. Our\nfindings may increase clinical awareness of the early clinical signs of PWS,\nenabling early diagnosis and start of multidisciplinary treatment.<\/p>\n\n\n\n

Conclusion<\/strong><\/p>\n\n\n\n

Our study revealed that 6 (66.7%)\nout of 9 children with PWS had birth defects.<\/p>\n\n\n\n

At ultrasound during pregnancy, we observed certain clinical features of\nthe fetus, including fetal intrauterine development\ndelay \u2013 5 (55.5%) and higher nuchal translucency measurement \u2013\n3 (33.3%).<\/p>\n\n\n\n

According to the checklist of autism spectrum\ndisorders (CASD), 3(33.3%)\nof the examined children with autism syndrome are at risk and require further\nmonitoring, and 5(55.5%)\nchildren scored 18-20 points, which indicates the presence of an autistic range\nand requires in-depth monitoring during diagnosis. <\/p>\n\n\n\n

A multisystem approach should\nbe applied to families with a child with PWS, which includes consultation with\ndoctors of various specialties, such as neurologists, genetics,\nendocrinologists, psychologists, ophthalmologists, nutritionists, etc.<\/p>\n\n\n\n

In cases if the children have signs of autism or developmental delay, they should undergo genetic counseling.<\/p>\n\n\n\n

Conflict of Interest<\/strong><\/p>\n\n\n\n

The authors have no conflicts of interest to declare. <\/p>\n\n\n\n

Funding Sources<\/strong> <\/p>\n\n\n\n

Authors state no funding involved.<\/p>\n\n\n\n

Literature<\/strong><\/p>\n\n\n\n

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