Printer Friendly

8q22.1 Microduplication Syndrome: Why the Brain Should Be Spared? A Literature Review cod c Case Report.

1. Introduction

Microduplication of chromosome 8q22.1 is an extremely rare genetic disorder with prevalent muscular-skeletal phenotype due to defect of the GDF6 and SDC2 genes. The muscular-skeletal features merely configure Leri's pleonosteosis (LP) phenotype, a very rare disorder first described in 1921 [1]. Few multigenerational families have been reported so far, and the prevalence is estimated as <1/10,00,000 [2].

Leri's pleonosteosis was originally described as a rare congenital rheumatic disease frequently overlapping with other muscoloskeletal diseases [1]. The overexpression of these genes dysregulates proteins of the extracellular matrix synthesis and transforming growth factor- (TGF-) j3 pathway [3]. Currently, it is assumed that the heterozygous microduplication of chromosome 8q22.1, encompassing GDF6 and SDC2 genes, has a causative role in the rheumatic signs of the disease [3]. The growth/differentiation factor-6 (GDF6) is a member of the transforming growth factor-beta (TGF-[beta]1) superfamily, required for normal formation of bones and joints in the limbs, skull, and axial skeleton [4]. Syndecan-2 (SDC2) gene is a member of the syndecan proteoglycan family who produces a transmembrane heparan sulfate proteoglycan. The syndecan-2 protein acts as an integral membrane protein playing a role in cell proliferation, cell migration, and cell-matrix interactions [5]. More recently, Western blot analysis also revealed markedly decreased inhibitory SMAD6 (mothers against decapentaplegic homolog 6) levels in patients with LP [3]. SMAD6 is an antagonist of signaling by TGF-beta-type 1 receptor superfamily members and acts as a mediator of TGF-beta and BMP anti-inflammatory activity [3].

The LP clinical phenotype is characterized by dismorphic facial features, abnormalities of hands and feet, skeletal malformations, short stature, and limitation of joint movements. Skeletal malformations can include brachydactyly, "spade-shaped" appearance, genu recurvatum, and abnormal enlargement of the cartilaginous structures that surround the upper portion of the spinal cord [6]. A review of the literature with a detailed report of four cases was provided by Watson-Jones in 1949 [7]. The author focused his attention only on skeletal symptoms of the disease. Around ten years later, Yeoman described the case of a 16-year-old girl having the muscular-skeletal features of the disease with no cognitive impairment (he described her as an "intelligent girl") [8]. A few years later (1959), Rukavina et al. reported a four-generation family with LP [9], and Booth observed a father and his son with the same condition [10]. In the 1980s, Hilton and Wentzel reported seven patients from the same family [11], and Friedman described two single cases [6]. Approximately 30 cases have been reported in the literature at the current state.

Most of the authors reported LP cases focusing their attention only on the somatic features (e.g., facial dimorphic features and skeletal and joins malformations). To the best of our knowledge, the only detailed description of psychiatric symptoms in LP was provided by Macayran et al. [12]. They presented a 7-year-old boy affected by LP and bipolar disorder. The child showed a speech-sound disorder and a highly pressured pattern of speech. He also displayed difficulty in sustaining attention, high levels of hyperactivity, low frustration tolerance, indiscriminate friendly and socially inappropriate behaviour toward adults. The cognitive assessment was performed by the Kaufman Assessment Battery for Children (K-ABC) [13] that showed a "mental process composite" score of 86 (-1 DS) at the age of 5 and 6. Nevertheless, one and a half years later, the mental process composite score decreased to 74 points (-2 DS). Thus the authors assumed that the patient had had a cognitive functioning regression. Additionally, he showed decreased need for sleep, flight of ideas and increased sexualized behaviour, in opposition to previous depressed mood episode. Cytogenetic analysis revealed a 46, XY, ins (15;8) karyotype with a duplication of 8q, confirmed by chromosome 8-specific subtelomere FISH analyses. Recently, a more complex case regarding a 14-year-old boy presenting both 142 Kb duplication in 8q22.1 and 252 Kb duplication in 22q11.2 was reported. The patient showed mild cognitive impairment (IQ 70) and attention deficit disorder. However, the presence of a double duplication in two different genomic regions makes it difficult to correlate the psychiatric features to the 8q22.1 duplication [14].

In the past few years several studies documented the systematic co-occurrence of psychiatric illnesses mental disorders and systemic diseases [15]. In particular, many genome-wide association studies (GWAS) have been conducted to identify genetic risk variants underlying psychiatric disorders [16]. Meanwhile the epidemiological observation of a frequent co-occurrence of autoimmune disorders such as rheumatoid arthritis (RA) and depression has focused the attention on genetic background underlying these comorbidities [17-19]. Furthermore, strong evidence for the existence of a genetic relationship and a pervasive pleiotropy between psychiatric disorders and immune disorders have been collected [20].

The present work describes an 8-year-old girl that showed a Leri's pleonosteosis phenotype associated with neurodevelopmental disorders and psychiatric symptoms.

2. Case Description

Written informed consent for publication was obtained by the patient's parents.

Our patient is an 8-year-old girl, with a positive family history for both skeletal malformations and bipolar disorders (BD). Her pre-perinatal history was uneventful. She was referred to our Unit because of learning difficulties and behavioural problems. The neurological examination did not show focal neurological deficits. Dysmorphic features were evident at the first observation. She showed several facial dimorphisms such as flat face, blepharophimosis, hypertelorism, broad nasal bridge, and high palate. Bones and joints defects were also evident: pectum excavatum, single transverse palmar crease, brachydactyly, flat foot, and stature below 25th percentile (Figure 1). Because of these features, she previously underwent genetic consultation and performed array-CGH analysis revealing a chromosomic 8q22.1-q22.3 duplication (hg19/96.846.254-101.630.576x3, 101.726.279x2) encompassing the GDF6 and SDC2 genes, inherited from her father. Thus, our 8-year-old girl presented with clinical and genetic features of Leri's pleonosteosis, within a larger microduplication involving different genes not strictly related to our patient phenotype. In particular, the hypothesis of autosomal recessive optic atrophy (OPA6) was excluded by a general ophthalmologic examination and a fundus examination, since the contiguous region 8q21.13-q22.1 is responsible for recessive optic atrophy [21].

She also met the DSM-5 criteria for attention-deficit/ hyperactivity disorder (ADHD), specific learning disorder, speech sound disorder, and developmental coordination disorder. In particular, she showed a highly pressured pattern of speech, difficulty in sustaining attention, high levels of activity, and low frustration tolerance. Furthermore, she presented a pattern of bipolar-like phenomena that did not meet the criteria for bipolar I, bipolar II, or cyclothymic disorder. Nevertheless, according to DSM-5 category, she met the criteria for the diagnosis of "other specified bipolar and related disorder" owing to the occurrence of hypomania episode without prior major depressive episode or a manic episode.

The clinical features are shared with both her father and her grandfather that present an overlapping duplication in the 8q22.1-q22.3 region. They show facial dimorphism (flat face, blepharophimosis, hypertelorism, and broad nasal bridge) and brachydactyly and are affected, respectively, by cyclothymic disorder and bipolar II disorder. Also her grandfather's brother received a diagnosis of bipolar II disorder. Unfortunately, he has never performed an array-CGH analysis, but he shows skeletal malformations consistent with Leri's disorder. Along paternal line of our patient, more members are affected by mood disorders associated with skeletal deformations. Unfortunately, none of them agreed to perform the array-CGH analysis, thus the information is incomplete to build a family tree chart. Nevertheless, the chromosome 8q22.1 micro-duplications were documented in our patient and his father and grandfather.

Our 8-year-old girl's developmental milestones had been mildly delayed. In particular, she presented a delayed achievement of the expressive language. Thus she started a speech-language therapy when she was 4-year-old and continued it for two years. During infancy, she also presented a divergent strabismus surgically treated at the age of 3 years. She also had genu recurvatum and hip developmental dysplasia (type-II Graf) within the first year of life. Our first neurological examination failed to detect major focal signs, but gross and fine coordination impairments with orofacial dyspraxia and speech phonological deficits were observed.

The behavioural observation revealed high levels of impulsivity and a persistently elated mood with increased activity and energy for most of the day. She often displayed restlessness, hyperactivity, and difficulty remaining focused. She also was more talkative than usual and prone to engage conversations with strangers in public, with an indiscriminately friendly approach and a high level of enthusiasm. On the whole, her social behaviour towards adults was often inappropriate. Furthermore, the conversation content appeared inappropriate to the contest with flight of ideas and abrupt shifts from one topic to another. She also showed amusing irrelevancies and theatrical mannerisms and an inflated self-esteem with uncritical self-confidence. Moreover, rapid shifts in mood over brief periods of time might occur. During these episodes, her mood became irritable and she presented decreased need for sleep, diminished ability to concentrate, inconclusiveness, and angry bursts when her wishes were denied.

The neuropsychological assessment included the cognitive profile (WISC IV) [22], visual perception and motor coordination (VMI) [23], executive functions (TOL) [24], and verbal and spatial memory (Corsi test) [25]. The IQ score was in the low average (total IQ score 88), with the lowest score in nonverbal and fluid reasoning (perceptual reasoning index = 80). A moderate impairment was revealed in visuospatial short-term working memory (Corsi backward span = 2; -1.89 SD) and in backward verbal span (digit backward span = 2; -1.29 SD). Planning ability was largely below the average (rule violations = T> 100, >-2 SD; number of additional moves = T> 100, >-2 SD, TOL), suggesting a poor mental planning and problem-solving skills. She also showed deficits in visual perception and motor coordination skills at the visual-motor integration test (VMI Beery, 1997; standard score = 78; 7th percentile). The reading and writing tests scored below the average (oral reading speed of a text: 0.88 syllables/seconds/-2 DS; number of errors = 14/5[degrees] percentile; writing errors: -2 DS). She lacked knowledge of spelling rules that made her enable to read and write complex words. In general, she showed difficulties in managing the aspect of phonological processing which underpins the acquisition ofliteracy. Working out meaning from a whole sentence was another of her weaknesses due to the working memory deficit. Instead, when dealing with words in isolation, she had less difficulty in comprehension. She also showed very low concentration and attention abilities. During the assessment, she had to be constantly refocused and prompted to continue. All in all, our patient's neurodevelopment and psychiatric symptoms caused a marked impairment, especially in social relationship and in academic performance.

3. Discussion

This case report describes an 8-year-old girl with micro-duplication of chromosome 8q22.1 characterized by Leri's pleonosteosis features, neurodevelopmental, and psychiatric disorders. This peculiar genotype-phenotype profile is shared with some other members of her family that display both musculoskeletal and psychiatric symptoms, associated with the microduplication of chromosome 8q22.1. This feature labels the co-occurrence between psychiatric symptoms and rheumatic condition sustained by a genetic disorder. It is also noteworthy that the psychiatric profile of all members of our family largely coincides with that of Macayran et al.'s patients [12], who had a larger duplication than patients with definite LP with muscular-skeletal manifestations only. Moreover, the 14-year-old boy reported by Tarsitano showed a more complex phenotype, but he presented both 142 Kb duplication in 8q22.1 and 252 Kb duplication in 22q11.2. According to all these observations, even if our patient presents a larger microduplication of chromosome 8q22.1 encompassing additional genes, none of them strictly explains her neuropsychiatric symptoms. Indeed, although prominent muscular-skeletal features resembling LP syndrome emerged in our patient, the occurrence of a complex neuropsychiatric phenotype as well as a larger duplication than the sole occurring in definite LP patients should suggest a different syndromic entity.

The two key questions of the present report are the following:

(1) Given that overexpression of GDF6 and SDC2 genes dysregulates proteins of the extracellular matrix synthesis and transforming growth factor (TGF)-[beta] pathway, why should the brain be spared from damage?

(2) Might the psychiatric comorbidity be underestimated in patients with LP features?

In recent years, an intensive research effort has focused on understanding the function of the TGF-[beta] superfamily in midbrain dopaminergic neuron development and their role in the molecular architecture that regulates the development of this brain region [26]. Older studies have suggested that TGF-[beta] 2 and TGF-[beta] 3 are physiological survival factors for developing midbrain dopaminergic neurons [27]. Furthermore, the TGF-beta isoforms -beta2 and -beta3, members of the TGF-beta superfamily, are expressed in the central nervous system and have an important role in embryonic patterning, cell migration, and neuronal transmitter determination [28]. The formation of neuronal connections in the developing brain is regulated by interactions of the cell surface with extracellular matrix molecules, soluble growth factors, and cell surface adhesion molecules. There is evidence for a role of syndecan-3 in cell-matrix adhesion in the developing central nervous system [29]. It is assumed that syndecan-3 functions as an HB-GAM receptor in the central nervous system [30]. HB-GAM (heparin-binding growth-associated molecule), also called pleiotrophin, is an 18 kDa secreted protein that is expressed in the central nervous system with a developmental time course that is essentially identical with that of syndecan-3 [31]. Purified HB-GAM promotes the attachment of a variety of cells and is a potent inducer of neurite outgrowth from embryonic or early postnatal cortical neurons [32]. Syndecan-3 is also present on the surface of cortical neurons spreading on surfaces coated with HB-GAM [32]. For all of these reasons appears at least counterintuitive to suppose that the brain is not involved in LP disease.

Such a complex model of 8q22.1 microduplication syndrome could be better explained considering the developmental trajectories of mental-physical comorbidity and the temporal association of mental disorders and physical diseases. In our patient, the very early onset of psychiatric symptoms largely contributes to explain the severity of the LP disease. Many diverse underling factors, both genetic and environmental, could have contributed to the onset of psychiatric symptoms that represent in our patients the prominent features of the LP phenotype. Notably, many linkage studies have implicated chromosome 8q24 as a promising positional candidate region in BP [33], but no evidence has been reported on the association between BP and 8q22.1 region. Only a life course perspective, not focused on selected mental or physical problems, could consent to provide a more accurate description of the whole clinical features. Therefore, we argue that the psychiatric comorbidity of LP disease could be underestimated.

The report provides a description of a possible wider phenotype of Leri's pleonosteosis disease, encompassing not only the physical signs but also psychiatric symptoms, and supports the conception of a more integrated mentalphysical health care approach. Further research is required to provide evidence of the association between rheumatic and psychiatric symptoms in LP. Nevertheless, the current report suggests that the psychiatric and neuropsychological LP patients' characteristics should be taken into consideration when making treatment decisions. Focusing the attention only on the rheumatic condition and musculoskeletal signs may lead to underrate the impact of psychiatric symptoms in the clinical management of these patients.

Furthermore, our report could be added to the large amount of previous reports that describe the correlation between genetic regions and disease risk for psychiatric and rheumatology disorders. The future research, particularly high-quality omics data, could provide an extraordinary opportunity to revisit the nature of the genetic connections between psychiatric and rheumatology disorders. More in general, the current understanding of the etiology of mental-physical comorbidity needs to be improved by theoretical models attempting to explain the trajectories of mental-physical comorbidity.

Conflicts of Interest

The authors declare that they have no conflicts of interest.


The authors want to thank the patient and her family for the contribution and the collaboration.


[1] A. Leri, "Une maladie congenitale et hereditarie de l'ossification: la pleonosteose familiale," Bulletins et memoires de la Societe Medicale des Hopitaux de Paris, vol. 45, pp. 1228-1230, 1921.

[2] Orphanet, "The portal for rare diseases and orphan drugs," 2018, Lng=EN&Expert=2900.

[3] S. Banka, S. A. Cain, S. Carim et al., "Leri's pleonosteosis, a congenital rheumatic disease, results from microduplication at 8q22.1 encompassing GDF6 and SDC2 and provides insight into systemic sclerosis pathogenesis," Annals of the Rheumatic Diseases, vol. 74, no. 6, pp. 1249-1256, 2015.

[4] S. H. Settle Jr., R. B. Rountree, A. Sinha, A. Thacker, K. Higgins, and D. M. Kingsley, "Multiple joint and skeletal patterning defects caused by single and double mutations in the Gdf6 and Gdf5," Developmental Biology, vol. 254, no. 1, pp. 116-130, 2003.

[5] J. J. Essner, E. Chen, and S. C. Ekker, "Syndecan-2," International Journal of Biochemistry, vol. 38, no. 2, pp. 152-156, 2006.

[6] M. Friedman, B. M. Lawrence, and D, G. Shaw, "Leeri's pleonosteosis," British Journal of Radiology, vol. 54, no. 642, pp. 517-518, 1981.

[7] R. Watson-Jones, "Leeri's pleonosteosis, carpal tunnel compression of the media nerves and Morton's metatarsalgia," Journal of Bone and Joint Surgery, vol. 31B, no. 4, pp. 560-571, 1949.

[8] P. M. Yeoman, "Leri's pleonosteosis," Proceedings of the Royal Society of Medicine, vol. 54, p. 275, 1961.

[9] J. G. Rukavina, H. F. Falls, J. F. Holt, and W. D. Block, "Leri's pleonosteosis; a study of a family with a review of the literature," Journal of Bone and Joint Surgery, vol. 41, no. 3, pp. 397-408, 1959.

[10] C. W. Booth, Personal Communication, Chicago, IL, USA, 1975.

[11] R. C. Hilton and J. Wentzel, "Leri's pleonosteosis," QJM: An International Journal of Medicine, vol. 49, pp. 419-429, 1980.

[12] J. F. Macayran, S. G. Brodie, P. N. Rao et al., "Duplication 8q22.1-q24.1 associated with bipolar disorder and speech delay," Bipolar Disorders, vol. 8, no. 3, pp. 294-298, 2006.

[13] A. S. Kaufman, M. R. O'Neal, A. H. Avant, and S. W. Long, "Introduction to the Kaufman Assessment Battery for Children (K-ABC) for pediatric neuroclinicians," Journal of Child Neurology, vol. 2, no. 1, pp. 3-16, 1987.

[14] M. Tarsitano, "Microduplications in 22q11.2 and 8q22.1 associated with mild mental retardation and generalized overgrowth," Gene, vol. 536, no. 1, pp. 213-216, 2014.

[15] A. Iacovides and M. Siamouli, "Comorbid mental and somatic disorders: an epidemiological perspective," Current Opinion in Psychiatry, vol. 21, no. 4, pp. 417-421, 2008.

[16] P. M. Visscher, M. A. Brown, M. I. McCarthy, and J. Yang, "Five years of gwas discovery," American Journal of Human Genetics, vol. 90, no. 1, pp. 7-24, 2012.

[17] M. Margaretten, L. Julian, P. Katz, and E. Yelin, "Depression in patients with rheumatoid arthritis description, causes and mechanisms," International Journal of Clinical Rheumatology, vol. 6, no. 6, pp. 617-623, 2011.

[18] T. Covic, S. R. Cumming, J. F. Pallant et al., "Depression and anxiety in patients with rheumatoid arthritis: prevalence rates based on a comparison of the depression, anxiety and stress scale (dass) and the hospital, anxiety and depression scale (hads)," BMC Psychiatry, vol. 12, no. 1, 2012.

[19] A. M. Rathbun, G. W. Reed, and L. R. Harrold, "The temporal relationship between depression and rheumatoid arthritis disease activity, treatment persistence and response: a systematic review," Rheumatology, vol. 52, no. 10, pp. 1785-1794, 2013.

[20] Q. Wang, C. Yang, J. Gelernter, and H. Zhao, "Pervasive pleiotropy between psychiatric disorders and immune disorders revealed by integrative analysis of multiple GWAS," Human Genetics, vol. 134, no. 11-12, pp. 1195-1209, 2015.

[21] F. Barbet, S. Gerber, S. Hakiki et al., "A first locus for isolated autosomal recessive optic atrophy (ROA1) maps to chromosome 8q," European Journal of Human Genetics: EJHG, vol. 11, no. 12, pp. 966-971, 2003.

[22] Wechsler, Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV), The Psychological Corporation, San Antonio, TX, USA, 2003.

[23] C. Y. Lim, P. C. Tan, C. Koh et al., "Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery-VMI): lessons from exploration of cultural variations in visual-motor integration performance of preschoolers," Child: Care, Health and Development, vol. 41, no. 2, pp. 213-221, 2015.

[24] T. Shallice, "Specific impairments of planning," Philosophical Transactions of the Royal Society of London, Part B, vol. 298, pp. 199-209, 1982.

[25] P.M. Corsi, "Human memory and the medial temporal region of the brain," Dissertation Abstracts International, vol. 34, no. 2, p. 891B, 1972.

[26] G. Masi, G. Perugi, C. Toni et al., "Attention-deficit hyperactivity disorder-bipolar comorbidity in children and adolescents," Bipolar Disorders, vol. 8, no. 4, pp. 373-381, 2006.

[27] H. Lazaratou, "Attention-deficit hyperactivity disorder or bipolar disorder in childhood?," Psychiatriki, vol. 23, no. 4, pp. 304-313, 2012.

[28] A. A. Nierenberg, S. Miyahara, T. Spencer et al., "Clinical and diagnostic implications of lifetime attention-deficit/ hyperactivity disorder comorbidity in adults with bipolar disorder: data from the first 1000 STEP-BD participants," Biological Psychiatry, vol. 57, no. 11, pp. 1467-1473, 2005.

[29] D. J. Carey, K. Conner, V. K. Asundi et al., "cDNA cloning, genomic organization, and in vivo expression of rat N-syndecan," Journal of Biological Chemistry, vol. 272, no. 5, pp. 2873-2879, 1997.

[30] E. Raulo, M. A. Chernousov, D. J. Carey, R. Nolo, and H. Rauvala, "Isolation of a neuronal cell surface receptor of heparin binding growth-associated molecule (HB-GAM). Identification as N-syndecan (syndecan-3)," Journal of Biological Chemistry, vol. 269, no. 17, pp. 12999-13004, 1994.

[31] H. Rauvala, A. Vanhala, E. Castren et al., "Expression of HBGAM (heparin-binding growth-associated molecules) in the pathways of developing axonal processes in vivo and neurite outgrowth in vitro induced by HB-GAM," Developmental Brain Research, vol. 79, no. 2, pp. 157-176, 1994.

[32] E. Raulo, I. Julkunen, J. Merenmies, R. Pihlaskari, and H. Rauvala, "Secretion and biological activities of heparin-binding growth-associated molecule. Neurite out growth-promoting and mitogenic actions of the recombinant and tissue-derived protein," Journal of Biological Chemistry, vol. 267, no. 16, pp. 11408-11416, 1992.

[33] P. Zandi, S. Zollner, D. Avramopoulos et al., "Family-based SNP association study on 8q24 in bipolar disorder," American Journal of Medical Genetics PartB, vol. 147, no. 5, pp. 612-618, 2008.

Antonella Gagliano, Erica Pironti, Francesca Cucinotta, Cecilia Galati, Roberta Maggio, Maria Ausilia Alquino, and Gabriella Di Rosa

Department of the Adult and Developmental Age Human Pathology, Unit of Child Neurology and Psychiatry, University Hospital of Messina, Messina, Italy

Correspondence should be addressed to Antonella Gagliano;

Received 13 February 2018; Accepted 12 April 2018; Published 12 July 2018

Academic Editor: Georgios D. Kotzalidis

Caption: Figure 1: (a, b) Facial picture of the 8-year-old girl showing facial dimorphism: flat face, blepharophimosis, hypertelorism, broad nasal bridge, and high palate. (c, d) Hands photograph showing bones and joints defects: single transverse palmar crease and brachydactyly. (e) The 8p22.1 microduplication and its coordinates in our patient.
COPYRIGHT 2018 Hindawi Limited
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2018 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Title Annotation:Case Report
Author:Gagliano, Antonella; Pironti, Erica; Cucinotta, Francesca; Galati, Cecilia; Maggio, Roberta; Alquino
Publication:Case Reports in Medicine
Date:Jan 1, 2018
Previous Article:A Case of Herpes Simplex Virus-1 Encephalitis from a Medicolegal Point of View.
Next Article:Total Plasma Exchange in Hypertriglyceridemia-Induced Pancreatitis: Case Report and Literature Review.

Terms of use | Privacy policy | Copyright © 2022 Farlex, Inc. | Feedback | For webmasters |