The authors would like to thank the WikiPathways curation team for helpful support. School of Medicine: Tulane Resident and Fellow Congress (TRFC), Employee's COVID-19 Information & Guidelines. Upon activation, NPY/AgRP neurons stimulate food intake, whereas POMC neurons reduce food intake. These symptoms are most likely caused by defects in the hypothalamus, but how they emerge remains unclear (Cassidy and Schwartz Citation1998; Myers etal. Those features include severe developmental delay, speech impairment, typical facial features and a distinctive behavioural phenotype that includes a happy appearance, excessive laughter, hyperactivity and easy excitability (Cassidy and Schwartz Citation1998; Williams etal. -, OKeefe C, McDevitt MA, Maciejewski JP. HHS Vulnerability Disclosure, Help Consult your healthcare provider or genetic counselor for more information on uniparental Figure modified after Burnett etal. Normally,you inherit1 copy of each chromosome pair from your biological mother, and the other copy of the chromosome pair from your biological father. If your child seems to have developmental delays or if your child has other signs or symptoms of Angelman syndrome, make an appointment with your child's doctor. This information is not intended as a substitute for professional medical care. A wide variety of health conditions are suspected to be regulated by such imprinting, including cancers, cognitive dysfunction, and respiratory, cardiovascular, reproductive, autoimmune, and neurobehavioral disorders (Weinhold Citation2006). PWS is caused by a deficiency of paternal gene expression and AS is caused by a deficiency of maternal gene expression. Citation1993), which contribute to the phenotypic appearance of the patients. In addition, microcephaly and seizures are common. Please enable it to take advantage of the complete set of features! If that section of the mother's chromosome #15 is deleted, only the father's section will be present, allowing AS symptoms to occur. Normally, only the maternal copy of the UBE3A gene is active in the brain. Accepted author version posted online: 09 Feb 2018. Citation2010; Judson etal. Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are examples of disorders that can be caused by uniparental disomy. Ghrelin is also involved in the secretion of growth hormone (GH), which will then be lower as well (Dimaraki and Jaffe Citation2006). In other words, UBE3A stimulates the expression of those genes. Angelman syndrome, like PWS, results from defects in one region of chromosome 15. Judson etal. They initially are slow feeders and appear undernourished. Studies on Ndntm2Stw mice showed that FEZ1 stimulates neurite and axonal outgrowth. The lack of NDN activity might be a major cause in this, but this cannot be confirmed by the current literature. Angelman syndrome is a genetic disorder. Angelman syndrome signs and symptoms include: People who have Angelman syndrome may also show the following features: Most babies with Angelman syndrome don't show signs or symptoms at birth. This could be another explanation for hyperphagia. UBE3A sequence analysis detects mutations in an additional ~11% of individuals. Citation2001). All rights reserved. ARF stimulates expression of p53, which can in turn cause apoptosis and G2/M arrest. Recent findings. and transmitted securely. They connected the affected hormones to symptoms of PWS, and covered a lot of them (Figure 7). A recent publication indicates that CBLN1 might also be a linking pin, although the molecular pathway is not known (Krishnan etal. Citation1993), although there are some hints that it may be involved in body fat generation in mice (Dhar etal. As with Angelman syndrome, PWS can also occur even . In PWS and AS, both genes are deleted, resulting in an impaired melanin synthesis pathway. Citation1993; Duker etal. Expression of GABRB3 was found in embryonic stem cells and neural crest stem cells (Delahanty etal. Leptin is secreted by adipose tissue in order to regulate fat storage (Myers etal. NHLH2 stimulates PCSK1 expression, and PCSK1 itself binds to a Ca2+ cofactor. Genetic imprinting suggested by maternal heterodisomy in nondeletion Prader-Willi syndrome. Loss of this 2-Mb domain on the paternal or maternal allele results in two neurogenetic disorders, Prader-Wile syndrome (PWS) or Angelman syndrome (AS), respectively. Always follow your healthcare professional's instructions. This deletion of a section Angelman syndrome signs and symptoms include: Developmental delays, including no crawling or babbling at 6 to 12 months Intellectual disability No speech or minimal speech Difficulty walking, moving or balancing well Frequent smiling and laughter Happy, excitable personality Sucking or feeding difficulty Trouble going to sleep and staying asleep Citation2008; Janssen etal. Accessibility Citation2009; Duker etal. Citation2013), and in the development of hypothalamic anorexigenic circuits (Maillard etal. Burnett etal. Citation2015). Citation2015). copies of a section of chromosome #15 from the mother. Nat Rev Genet. (Citation2017) suggest that the major neuroendocrine features of PWS are due to PCSK1 deficiency. The most common etiology is deletion of the maternal or paternal 15q11q13 region. Citation2016). They initially are slow BBS4 is thought to interact with the dynein microtubule-based molecular motor, in order to transport the scaffold protein PCM1 to centrosomal satellites, which enables the formation of the centrosomal microtubule organising centre. 1986;23(793809):793809. The most common etiology is deletion of the maternal or paternal 15q11q13 region. See this image and copyright information in PMC. PWS and AS are caused by the loss of function of imprinted genes in proximal 15q. Methylation is the first line for molecular diagnostic testing; MS-MLPA is the most sensitive test. This content does not have an Arabic version. In AS, patients suffer from a more severe developmental delay, they have a distinctive behaviour that is often described as unnaturally happy, and a tendency for epileptic seizures. Cited by lists all citing articles based on Crossref citations.Articles with the Crossref icon will open in a new tab. Genetic disorders and dysmorphic conditions. AS can also occur even when chromosome #15 is inherited normally1 chromosome coming from each parent. Any hypotheses about involvement of distal regulators within the PWS region, DNA loops or microRNA remain speculative. General information on PWS and AS, the involved genes and their molecular interactions was obtained through literature research using PubMed. As GABRB3 encodes a subunit of the GABA(A) receptor, and stimulates transcription of two other subunits (GABRA5 and GABRG3), loss of it will interfere with the function of this receptor. 6 Testing for hypothyroidism, including thyroid-stimulating hormone (TSH) and free thyroxine (T4) tests, and testing for diabetes are recommended to monitor for comorbidities. Due to methylation patterns, different genes are responsible for the two distinct phenotypes resulting in the disorders. SNORD116@ is found to be sufficient to elicit hypotonia in neonates, as well as developmental delay in a later stage, but the mechanism of action has yet to be found. 1987;28(4):829838. This was concluded due to the fact that wild-type mice had far more melanocytes in the last two out of four maturation stages than mice lacking one or two copies of GABRB3. Citation2005). SNORD115@ is another gene cluster that is located in the PWS region (Figure 8). It would be interesting to see how this effect is influenced by other pathways, so that puberty is suppressed. Citation1999). Epilepsy features might be related to the seizures that are seen in AS, yet they are not reported in PWS. It is known that disturbance of the central serotonin system, specifically a reduction in serotonin availability or efficacy, can cause hyperphagia (Garfield and Heisler Citation2009). Besides, PWS patients also suffer from various complications including hypogonadism and infertility, growth hormone (GH) deficiency, delayed puberty, disturbance in circadian rhythm, hypopigmentation, osteoporosis, mild cognitive impairment, delay in motor and language development, and several characteristic behaviour types, facial features, and body habitus (Cassidy and Schwartz Citation1998). (Citation2017) found that the expression of several tumour-suppressor genes was decreased in UBE3A-deficient mouse fibroblasts. The PWS/AS pathway was constructed using PathVisio software (version 3.2.4) (van Iersel etal. Angelman syndrome results when a baby inherits both copies of chromosome #15 from the father (rather than one from the mother . FEZ1 is then thought to regulate neurite axonal outgrowth and axonal transport. Disturbed GNRH1 expression is an important factor, and both NDN and SNORD116@ could be contributing to the delay of development as their downstream pathways interfere with these pathways. Citation2007). The involved genes and their downstream pathways in detail, https://doi.org/10.1080/15622975.2018.1439594, http://www.wikipathways.org/instance/WP3998, http://www.wikipathways.org/instance/WP3998_r92786, http://www.reactome.org/PathwayBrowser/#/R-HSA-72163, https://www.ebi.ac.uk/gxa/genes/ENSG00000128739?bs=%7B%22homo%20sapiens%22%3A%5B%22ORGANISM_PART%22%5D%7D&ds=%7B%22kingdom%22%3A%5B%22animals%22%5D%7D#baseline. Prader-Willi and Angelman syndromes are 2 clinically distinct disorders associated with multiple anomalies and mental retardation. GeneReviews. and at least one of c c c and d d d, are non-zero, show that a d = b c a d=b c a d = b c is both a necessary and sufficient condition for the equations. Prader-Willi syndrome (PWS), on the other hand, can result when a baby inherits both copies of a section of chromosome #15 from the mother. Here, we compare and discuss the mechanisms, pathophysiology, clinical features, and management of the two imprinting disorders, PWS and AS. The exact mechanism through which this occurs is unknown. Bethesda, MD 20894, Web Policies Angelman is usually UBE3A. If that section of the father's chromosome #15 is deleted, only the mother's section will be present, allowing PWS symptoms to occur. . Diagram of maternal (MAT; top) and paternal (PAT; bottom) regions of human chromosome 15q11-q13. Absence of SNORD115@ would cause more alternate splicing and adenosine-to-inosine RNA editing, resulting in truncated and dysfunctional receptors (Canton etal. Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are genetic imprinting disorders resulting from absent or reduced expression of paternal or maternal genes in chromosome 15q11q13 region, respectively. Results usually available in 7-10 working days. This region contains several genes, depicted in Figure 1 (Driscoll etal. Online Medical Reviewer: Chad Haldeman-Englert MDDonna Freeborn PhD CNM FNPRaymond Kent Turley BSN MSN RN. The most common etiology is deletion of the maternal or paternal 15q11q13 region. Citation2010). of laughter. 8600 Rockville Pike -, Butler MG, Meaney FJ, Palmer CG, Opitz JM, Reynolds JF. In a few cases, Angelman syndrome is caused when two paternal copies of the gene are inherited, instead of one from each parent. Citation2010). The INK4/ARF locus also encodes ARF, which can cause apoptosis and G2/M arrest. 1998-2023 Mayo Foundation for Medical Education and Research (MFMER). Advertising revenue supports our not-for-profit mission. For metabolites, ChEBI (Hastings etal. There are three common breaking points; the deletion occurs from either breaking point 1 or 2 to breaking point 3. Uniparental This mechanism could also play a role in the development of these disorders in humans, but this has not yet been proven. Figure 3 shows how MKRN3 inhibits expression of the gonadotropin-releasing hormone (GNRH1), either directly or via the neurokinin B (NKB) pathway (Navarro etal. Angelman syndrome Insights into a rare neurogenetic disorder. 1989 Nov 16;342(6247):281-5. doi: 10.1038/342281a0. To conclude, in this study a collection and presentation of currently available knowledge of the molecular interactions and downstream pathways of genes that are involved in PWS and AS is presented. This results in impaired prohormone processing, and as such a decrease in active hormone levels (Brange and Langkjoer Citation1993; Burnett etal. Their annotations were derived primarily from Ensembl or Entrez Gene. Angelman syndrome can result when a baby inherits both copies of a section of chromosome #15 from the father (rather than1 from the mother and1 from the father). The function of SNURF is currently unclear, hence the gap annotation in the PWS pathway (Figure 5). Pediatrics. allowing PWS symptoms to occur. To learn about our use of cookies and how you can manage your cookie settings, please see our Cookie Policy. 2018. https://www.clinicalkey.com. MAGEL2 and NDN interact through an unknown mechanism with BBS4, which then facilitates the formation of the centrosomal microtubule organising centre. People with Angelman syndrome (AS) have an unusual facial appearance, short stature, severe intellectual disability with a lack of speech, stiff arm movements, and a spastic, uncoordinated walk. . 1998 Oct 6 [updated 2023 Mar 9]. Prader-Willi (PWS) and Angelman syndrome (AS) are distinct neurogenetic disorders caused by chromosomal deletions, uniparental disomy or loss of the imprinted gene expression in the 15q11-q13 region. The feeding problems improve after infancy. Results: A pathway visualisation was created and uploaded to the open pathway database WikiPathways covering all molecular pathways that were found. Epigenetics. The authors report no other conflicts of interest in this work. Citation2016). Klinefelter's syndrome b) Prader-Willi syndrome c) Down syndrome d) Fragile-X syndrome. Citation1997; Garfield etal. Before They may have seizures and often have inappropriate outbursts of laughter. The relation of the cleft palate and hyperactive behaviour to these two syndromes remains open to debate. The offspring could be at risk of being born with PWS or with Angelman syndrome. All of the level decreases seen here are caused by a PCSK1, which is in turn caused by a loss of the SNORD116 gene cluster. Assume the regioselectivity is consistent with the Zaitsev rule. . This can lead to epilepsy, cleft palate and hypersensitive behaviour, especially in the case of AS together with the loss of UBE3A induced dysfunction of the GABAergic neurons (Greer etal. This is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, reproduction in any medium, provided the original work is properly cited. Prader-Willi syndrome and Angelman syndr . friederike.ehrhart@maastrichtuniversity.nl, 3. . In this way, the reduced volume of the PVN, and the reduced activation of and secretion by POMC neurons, might have a relation. National Institute of Neurological Disorders and Stroke. Entrez Gene (Maglott etal. Methylation is the first line for molecular diagnostic . sharing sensitive information, make sure youre on a federal An official website of the United States government. Mayo Clinic; 2019. Register to receive personalised research and resources by email. A lack of GHRH, and consequently low GH levels, might be responsible for the short stature seen in PWS patients, and finally a low insulin level could cause type 2 diabetic features. Research in mice revealed that loss of the SNORD116 gene cluster (annotated as SNORD116@), without interruption of any other genes, causes a reduction of NHLH2 and prohormone convertase PC1 (PCSK1) expression (Burnett etal. SNURF-SNRPN is a bicistronic gene, encoding two different proteins (Driscoll etal. Bookshelf Citation1993; Duker etal. and type 2 diabetes. Kotagal S (expert opinion). Many PWS features are connected to a decrease of a certain hormone level. Citation2005). Citation2017). Angelman syndrome. FOIA uncoordinated walk. Mayo Clinic. People with Angelman syndrome often smile and laugh frequently, and have happy, excitable personalities. Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are genetic imprinting disorders resulting from absent or reduced expression of paternal or maternal genes in chromosome 15q11q13 region, respectively. The effect of SNURF is currently unknown, which is indicated with a gap annotation. Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are examples of disorders that can be caused by uniparental disomy. GABRB3 itself is involved in stem cell differentiation into melanocytes. Wheeler AC, et al. Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are genetic imprinting disorders resulting from absent or reduced expression of paternal or maternal genes in chromosome 15q11q13 region, respectively. The dashed lines indicate that the exact mechanism is not clear; there might be more steps involved. SNURF-SNRPN pathway section. ARC is a synaptic protein which is responsible for the trafficking of a GABA receptor subtype. genomic imprinting affects both female and male offspring. Two interesting rare disorders that are subject to both (genetic variation and epigenetics) are Prader-Willi syndrome (PWS) and Angelman syndrome (AS). Figure 5. Influence of the Prader-Willi syndrome imprinting center on the DNA methylation landscape in the mouse brain. Albright hereditary osteodystrophy), uniparental chromosome 14 disomy, chromosome 6q24-related transient neonatal diabetes . Monitoring in Prader-Willi Syndrome Insulinlike growth factor 1 (IGF-1) and growth hormone status testing is recommended to monitor the success of growth hormone treatment. Prader-Willi syndrome (PWS), on the other hand, can result when a baby inherits both copies of a section of chromosome #15 from the mother. Due to methylation patterns, different genes are responsible for the two distinct phenotypes resulting in the disorders. Citation2011). Citation1997). of the maternally inherited chromosome is the most common cause of AS. Disorders include Prader-Willi and Angelman syndromes, the first examples of imprinting errors in humans, chromosome 15q11.2-q13.3 duplication, Silver-Russell syndrome, Beckwith-Weidemann syndrome, GNAS gene-related inactivation disorders (e.g. On top of that they also often exhibit mild cognitive impairment and a delay in motor and language development. Citation2017). Epub 2015 Jun 11. Normally,you inherit1 copy of each chromosome pair from your biological mother, and the other copy of the chromosome pair from your biological father. doi:10.1182/blood-2009-10-201848 The syndrome is due to the loss of expression of several genes encoded on the proximal long arm of chromosome 15 (15q11.2-q13). First, all genes involved in PWS and AS were visualised as data nodes and annotated with their database identifiers. In a normal situation, SNORD116@ and NHLH2 stimulate PCSK1 expression. If MAGEL2 and NDN are lost, most of the problems that arise involve the development of neurons (Figure 4). Genetic testing must confirm the Prader-Willi syndrome diagnosis. Yet, both processes are not confirmed with certainty. Consult your healthcare provider or genetic counselor for more information on uniparental disomy. As with Angelman syndrome, Many of them are rare diseases, meaning that they occur in less than 1,500 (USA), 2,000 (EU) or 2,500 (Japan) individuals. Am J Med Genet. Careers. The https:// ensures that you are connecting to the This was found to cause several disorders in mice, including epilepsy, cleft palate and hyperactive behaviour. Pagon RA, et al., eds. Prader-Willi syndrome (PWS), on the other hand, can result when a baby inherits both What is Angelman syndrome? Citation1999; Lee etal. The effect of SNRPN on symptom level is unknown, which is notable, because this gene was long believed to be causing most of the symptoms. Citation2008). With advancing medical and scientific knowledge, researchers have more data, information and tools to decipher the cause for diseases. Figure 2. As for SNURF, there is nothing to be displayed in a pathway. The changing purpose of Prader-Willi syndrome clinical diagnostic criteria and proposed revised criteria. Prader-Willi syndrome = maternal imprinting or maternal UPD Angelman syndrome = paternal imprinting or paternal UPD Both conditions are on chromosome 15 but are not reciprocal imprints/UPDs of the same gene. What is AS: Diagnosis. Furthermore, the FEZ1 orthologue UNC-76 in Drosophila melanogaster interacts with the molecular motor kinesin, which is essential for axonal transport (Kuroda etal. You receive your pairs of genes from your parents one copy from your mother (maternal copy) and the other from your father (paternal copy). 2001 Nov;108(5):E92. UC San Diego | School of Medicinetoday = new Date(); document.write("Copyright © ", today.getFullYear()); UBE3A mutations or dysregulations were observed in several intellectual disorders, neurodevelopmental delay, epilepsy and autism spectrum disorders (Zhang etal. The ultimate result of UBE3A action here is the inhibition of E2F1 expression, and thus G1/S progression. Citation1993; Duker etal. Click Below to Contact one example is using MLPA where the overall sensitivity is greater than . What is maternal vs paternal imprinting? Incorrect development of the brain, and possibly the hypothalamus, find an origin in the loss of both MAGEL2 and NDN. Babies born with PWS have poor muscle tone and a weak cry. Angelman syndrome (AS) was first reported by Dr. Harry Angelman in 1965 and characterized by severe intellectual disability, ataxia, jerky arm movements, absent or very limited speech, inappropriate laughter, and a particular facial appearance. Did you know that with a free Taylor & Francis Online account you can gain access to the following benefits? A deletion of the HBII-85 class of small nucleolar RNAs (snoRNAs) is associated with hyperphagia, obesity and hypogonadism, Beyond epilepsy and autism: disruption of GABRB3 causes ocular hypopigmentation, A novel ATPase on mouse chromosome 7 is a candidate gene for increased body fat, Role of endogenous ghrelin in growth hormone secretion, appetite regulation and metabolism, Paternally inherited microdeletion at 15q11.2 confirms a significant role for the SNORD116 C/D box snoRNA cluster in Prader-Willi syndrome, Rett syndrome - biological pathways leading from MECP2 to disorder phenotypes, Reduced abundance of the E3 ubiquitin ligase E6AP contributes to decreased expression of the INK4/ARF locus in non-small cell lung cancer, Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT2C receptor mediated appetite, Pharmacological targeting of the serotonergic system for the treatment of obesity, Gene structure, DNA methylation, and imprinted expression of the human SNRPN gene, The Angelman syndrome protein Ube3A regulates synapse development by ubiquitinating arc, Angelman syndrome: etiology, clinical features, diagnosis, and management of symptoms, The ChEBI reference database and ontology for biologically relevant chemistry: enhancements for 2013, The human aminophospholipid-transporting ATPase gene ATP10C maps adjacent to UBE3A and exhibits similar imprinted expression, Mice devoid of gamma-aminobutyrate type A receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior, GABAergic neuron-specific loss of Ube3a causes angelman syndrome-like EEG abnormalities and enhances seizure susceptibility, The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review, Molecular interaction map of the mammalian cell cycle control and DNA repair systems, Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1, Mammalian homologue of the Caenorhabditis elegans UNC-76 protein involved in axonal outgrowth is a protein kinase C zeta-interacting protein, PathVisio 3: an extendable pathway analysis toolbox, Brain serotonin system in the coordination of food intake and body weight, Essential role for the Prader-Willi syndrome protein necdin in axonal outgrowth, A formal MIM specification and tools for the common exchange of MIM diagrams: an XML-Based format, an API, and a validation method, Entrez Gene: gene-centered information at NCBI, Loss of Magel2 impairs the development of hypothalamic anorexigenic circuits, Magel2 is required for leptin-mediated depolarization of POMC neurons in the hypothalamic arcuate nucleus in mice, Annotating cancer variants and anti-cancer therapeutics in reactome, Necdin, a Prader-Willi syndrome candidate gene, regulates gonadotropin-releasing hormone neurons during development, Leptin concentrations in Prader-Willi syndrome before and after growth hormone replacement, Regulation of NKB pathways and their roles in the control of Kiss1 neurons in the arcuate nucleus of the male mouse, Expression atlas update-an integrated database of gene and protein expression in humans, animals and plants, WikiPathways: pathway editing for the people, DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants, Reduced gamma-aminobutyric acid is associated with emotional and behavioral problems in Prader-Willi syndrome, Chapter 1, 4, 8, 23, Human hypothalamus: basic and clinical aspects, part 2, The p75 neurotrophin receptor interacts with multiple MAGE proteins, UniProt: the universal protein knowledgebase, Presenting and exploring biological pathways with PathVisio, The BridgeDb framework: standardized access to gene, protein and metabolite identifier mapping services, Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis, Clinical and genetic aspects of Angelman syndrome, Haploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech delay, and dysmorphic features, The World Journal of Biological Psychiatry. Figure 1. (Citation2016) showed that SNORD115@ is involved in the processing of pre-RNA of this receptor. The last pathway section contains four genes that are involved in PWS as well as in AS (Figure 10). This latter development happens in 70% of PWS cases. On top of that, patients with AS exhibit gait ataxia, tremulousness of the limbs, hypertonia and seizures. FEZ1 is involved in downstream effects on neurons. Citation2010). Francesca Torriani, MD 619-471-9045. When expression of OCA2 decreases, the melanin biosynthesis pathway is disturbed, leading to hypopigmentation. The construction of the PWS and AS pathway, 4. Hypogonadism is present in both males and females. Jan. 20, 2020. The overeating often results in rapid weight gain,obesity, and type 2 diabetes. Orphanet Journal of Rare Diseases. People with Angelman syndrome (AS) have an unusual facial appearance, short stature,severe intellectual disability with a lack of speech, stiff arm movements, and a spastic, uncoordinated walk. The coloured genes are those which are important for disease aetiology. Hyperphagia is considered the most important symptom of PWS due to its consequence of obesity, which leads to early death. official website and that any information you provide is encrypted WikiPathways, is a user-curated database that allows the collection, visualisation and publishing of new biological pathways by both (bio)medical professionals and bioinformaticians. Online pathway databases like KEGG, Reactome and WikiPathways provide this information and allow use of these pathways to analyse high-throughput transcriptomics, proteomics or metabolomics data (Pico etal. Prader-Willi Syndrome (PWS)is characterized by severe hypotonia and feeding difficulties in early infancy, followed in later infancy or early childhood by excessive eating and gradual development of morbid obesity, unless externally controlled.
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