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'{{refimprove|date=November 2018}} {{inline|date=November 2018}} {{Infobox medical condition | name = Helsmoortel-Van der Aa syndrome | synonyms = | image = Autosomal dominant - en.svg | caption = Autosomal dominant pattern is the inheritance manner of this condition | pronounce = | field = | symptoms = | complications = | onset = | duration = | types = | risks = | diagnosis = | differential = | prevention = | treatment = | medication = | prognosis = | frequency = | deaths = }} '''''Helsmoortel-Van der Aa syndrome''''' is a condition caused by mutations in the activity-dependent neuroprotector homeobox ([[ADNP (gene)|ADNP]]) gene.<ref name=VanDijck2018>{{cite journal | vauthors = Van Dijck A, Vulto-van Silfhout AT, Cappuyns E, van der Werf IM, Mancini GM, Tzschach A, Bernier R, Gozes I, Eichler EE, Romano C, Lindstrand A, Nordgren A, Kvarnung M, Kleefstra T, de Vries BB, Küry S, Rosenfeld JA, Meuwissen ME, Vandeweyer G, Kooy RF | display-authors = 6 | title = Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP | journal = Biological Psychiatry | date = March 2018 | pmid = 29724491 | doi = 10.1016/j.biopsych.2018.02.1173 }}</ref> This condition is rare with <100 cases described up to 2018. ==Genetics== This condition is caused by mutations in the ADNP gene. This gene is located on the long arm of [[chromosome 20]] (20q13.13). ==Pathogensis== The ANDP gene is involved in the [[autophagy]] pathway. Its precise role in this process is under active investigation. ==Clinical features== ADNP SYNDROME SUMMARY ADNP syndrome, also known as Helsmoortel-VanDerAa syndrome (HVDAS) is a complex neuro-developmental genetic disorder caused by a change (mutation or partial deletion) in the ADNP gene. ADNP syndrome can affect the neurological, cardiovascular, endocrine, immune, musculoskeletal and gastrointestinal systems, as well as muscle tone (hypotonia), vision, hearing, growth, feeding and sleep. Developmentally, it can cause delays in intelligence, delayed development of speech, speech apraxia or absent speech and global motor planning delays, (including gross motor, fine motor and oral motor). It causes behavior disorders such as Autism Spectrum Disorder (ASD) in a substantial proportion of cases. In fact, it is estimated: ADNP to be mutated in at least .17% of genetic autism cases, making it one of the most frequent ASD-associated genes known to date. SIGNS AND SYMPTOMS Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about ADNP syndrome is not fully understood. Therefore, it is important to note that every child is unique and that affected individuals may not have all of the symptoms discussed below. Many infants present with hypotonia / low or week muscle tone (78%). Infants may also present with feeding difficulties. Oral motor dysfunction such as poor sucking and chewing and hypotonia are often seen together in children with ADNP syndrome. This contributes to causing the majority of infants to experience feeding difficulties (83%). Swallowing problems may also be seen and there can be a risk of aspiration. Many children who experienced oral motor dysfunction early on develop apraxia of speech and or dyspraxia. The most common characteristics found in those with ADNP syndrome are developmental delays (100%), intellectual delays (100%), complex motor planning delays (96%) delayed or absent speech (98%) and autism spectrum disorder including autistic features (93%). Developmental and motor delays are usually seen early on. Missed milestones such as delays in sitting, holding up ones head, crawling and walking are seen in infancy and children are usually diagnosed with mild to severe global developmental and global motor planning delays. Walking independently is often delayed until a few years later in childhood and children may have an abnormal gait. Children with ADNP syndrome in their younger years tend to be easily amused with frequent smiling and laughing and have a very happy demeanor similar to Angleman syndrome. This often delays diagnosis for behavior disorders such as autism even when the child displays many autistic features early in life. Sleep disorders can also develop, including sleep apnea, frequent waking throughout the night as well as early waking. Many children have tonsils and adenoids removed to attempt to remedy some of the sleep issues. As children age they may exhibit mild to severe intellectual disability. There are often delays in developing speech. Some children with ADNP syndrome may not be able to speak while others speak a few words or in short sentences. Apraxia and other oral motor disorders specifically affecting the motor planning of the tongue appear to cause the most difficulty in the majority of the non-verbal children. The majority of affected children may meet the criteria for autism spectrum disorder and may exhibit poor social interaction and mild to severe repetitive (stereotypic) behaviors such as repetitive speech, rocking back and forth, hand flapping, hand clapping, rubbing fingers or snapping fingers (93%). They often have an obsession for music and water play. Children with ADNP syndrome often seek direct “adult” interaction but limited to no direct interest in interacting with other children. Specifically, at a very young age they appear to enjoy direct social interactions with adults, and often smile, laugh and make eye contact. This is atypical for autism but it is very typical for ADNP syndrome. This often delays the autism diagnosis even when the child displays many autistic features at a young age. Sensory processing disorder (both seeking and avoiding) is often seen (67%), with oral sensory seeking being the most prevalent. Because of this, children tend to lick their hands or other objects often, chew on non-edible items, gag, and put objects in their mouth. They also tend to place tablets and other lit objects or devises directly in front of their eyes or ears for stimulation. In addition to autism and sensory processing disorder, children may have a variety of behavioral issues including attention deficit hyperactivity disorder, obsessive compulsive disorder, temper tantrums and aggression, mood disorders, and anxiety. Cerebral imaging shows structural brain abnormalities in slightly over half of the patient population (56%). Other neurological problems may exist. Individuals with ADNP syndrome may develop seizures (16%). Many parents report absent like seizures as infants along with breath holding episodes. Reported brain abnormalities include wide ventricles( 29%), cerebral atrophy (18%), delayed myelination (9%) and white matter lesions (8%). Approximately 50% of children with ADNP syndrome have had one or more episodes of developmental regression of speech. Children with ADNP syndrome often have a high pain threshold (64%). Many parents report that their child does not seem to feel pain, some reporting fractures with no sign of uncomfortableness or distress. Low perception of pain in conjunction with communication issues can make it difficult for parents to know when their child has pain or an injury. Gastrointestinal symptoms are common. Affected individuals can develop backflow of stomach acids into the esophagus (gastroesophageal reflux). This has been reported as mild to severe. Some children require the placement of a feeding tube due to severe feeding problems. Episodes of chronic constipation and diarrhea are seen in almost all children with ADNP syndrome. Other symptoms include cyclic vomiting, delayed digestion, and irritable or inflammatory bowel conditions. Some children as they grow past the toddler years have an abnormal increased appetite and have difficulties feeling full (hyperphagia), similar to Prader Willi syndrome. This can lead to excessive weight gain. Some children also develop an abnormally increased desire to drink water. Some affected individuals may have congenital heart defects (38%). Ventricle or atrial septal defect is a common heart defect in ADNP syndrome. Additional congenital heart defects that have been reported in ADNP syndrome. Affected individuals have distinctive facial features prominent forehead, high hairline, droopy eyelids (ptosis), thin upper lip, broad nasal bridge, malformed ears, eyes that are farther apart than normal (hypertelorism), and crossed eyes (strabismus). Affected individuals may see objects that are farther away clearer than they see objects that are close up (farsightedness or hypermetropia). Cortical Vision Impairment has also been seed in multiple reported cases. Some infants experience early eruption of their baby (deciduous or primary) teeth, showing a full set of baby teeth by their first birthday, including molars. This is not seen in any other known syndrome making it unique to ADNP syndrome. The teeth may be abnormally small, jagged, and discolored. Because of early tooth eruption, some children develop tooth decay as toddlers due to the decrease in enamel. Some affected individuals have abnormally small pinkies that are fixed or ‘locked’ in a bent position (clinodactyly). Certain joints of fingers may be abnormally prominent. Additional symptoms include recurrent infections, especially upper respiratory and urinary tract. These recurrent infections may indicate an underlying problem with the immune system. Parents report that their children spike fevers extremely fast and they have difficulty regulating their body temperature and many have cold hands and feet. Some children exhibit growth delays and will be shorter than expected for their age and gender (short stature). Some children have tended to develop truncal obesity, in which the trunk of the body is affected as opposed to the arms and legs. Some have abnormally loose (lax) joints that have a larger range of motion than normal (hyperlaxity) and abnormal sideways curvature of the spine (scoliosis). ==Diagnosis== This is made by sequencing the ADNP gene. ==Treatment== Treatment is symptomatic. This may include speech, occupational, and physical therapy and specialized learning programs depending on individual needs. Treatment of neuropsychiatric features may also be needed. Nutritional support is sometimes needed. Treatment of the ophthalmologic and cardiac finding that may co exist is also indicated. ==History== The gene was described in 1999. ===Notes=== ADNP has been associated with abnormalities in the autophagy pathway in [[schizophrenia]].<ref name=Sragovich2017>{{cite journal | vauthors = Sragovich S, Merenlender-Wagner A, Gozes I | title = ADNP Plays a Key Role in Autophagy: From Autism to Schizophrenia and Alzheimer's Disease | journal = BioEssays | volume = 39 | issue = 11 | pages = 1700054 | date = November 2017 | pmid = 28940660 | doi = 10.1002/bies.201700054 }}</ref> == References == {{reflist}} {{Medical resources | DiseasesDB = | ICD10 = | ICD9 = | ICDO = | OMIM = | MedlinePlus = | eMedicineSubj = | eMedicineTopic = | MeshID = | GeneReviewsNBK = | GeneReviewsName = }} [[Category:Genetic diseases and disorders]] [[Category:Rare syndromes]] [[Category:Autosomal dominant disorders]]'