Rubinstein – Taybi in Syndrome a Peruvian patient with mild mental retardation: A case report / Síndrome de Rubinstein - Taybi em um paciente Peruano com leve retardo mental: Um relato de caso

(1)

Braz. J. of Develop.,Curitiba, v. 6, n. 8, p. 63905-63914 aug. 2020. ISSN 2525-8761

Rubinstein – Taybi in Syndrome a Peruvian patient with mild mental

retardation: A case report

Síndrome de Rubinstein - Taybi em um paciente Peruano com leve retardo

mental: Um relato de caso

DOI:10.34117/bjdv6n8-717

Recebimento dos originais: 08/07/2020 Aceitação para publicação: 31/08/2020

Pedro Teixeira Meireles

Medicine Course

University of Uberaba, Uberaba, MG, Brazil

Address: Av. Nenê Sabino, 1801, Bairro Universitário - Uberaba/MG CEP. 38.055-500 E-mail: teixeira.pedro98@hotmail.com

Mateus Borges Soares

Medicine Course

Address: Av. Nenê Sabino, 1801, Bairro Universitário - Uberaba/MG CEP. 38.055-500 E-mail: mateusbgsoares@gmail.com

Diego Rodrigues Naves Barbosa Lacerda

Medicine Course

Address: Av. Nenê Sabino, 1801, Bairro Universitário - Uberaba/MG CEP. 38.055-500 E-mail: diego_lacerda93@hotmail.com

Bruno Belmonte Martineli Gomes

Biomedicine

University of São Paulo, Ribeirão Preto, SP, Brazil

Address: Rua Nossa Senhora das Dores 811, Serrana-SP, CEP: 14150-000 E-mail: brunobmgomes@hotmail.com

Eduardo Elias Vieira de Carvalho

PhD in Clinical Medicine - University of São Paulo

Professor in Department of Applied Physical Therapy, Federal University of Triângulo Mineiro, Uberaba, MG, Brazil

Address: Rua Vigário Carlos - 100, Nossa Senhora da Abadia, 38025350 - Uberaba, MG - Brasil. E-mail: eduardo.carvalho@uftm.edu.br

Ana Karina Marques Salge

PhD in Helth Science - Federal University of Triângulo Mineiro Professor in Nurse Faculty of Federal University od Goiás - FEN/UFG

Address: Rua 227, Q. 68, S / N - Setor Leste Universitário, Goiânia - GO, 74605-080 E-mail: anasalge@gmail.com

(2)

George Kemil Abdalla

PhD in Helth Science - Federal University of Triângulo Mineiro Professor in Faculty of Human Talents - FACTHUS

Address: Av. Tonico dos Santos, 333 - Jardim Induberaba, Uberaba - MG, 38040-000 E-mail: gkabdalla@facthus.edu.br

Douglas Reis Abdalla

DPhD in Helth Science - Federal University of Triângulo Mineiro and PhD in Medical Sciense - University of Antwerp/Belgium

Professor in Faculty of Human Talents - FACTHUS

Address: Av. Tonico dos Santos, 333 - Jardim Induberaba, Uberaba - MG, 38040-000 E-mail: drabdalla@facthus.edu.br

ABSTRACT

Rubisntein-Taybi syndrome is of genetic origin, caused by a mutation in the CREBBP gene, which undergoes classic phenotypic changes and changes in neuropsychomotor development. In this sense, this article aims to report the case of a Peruvian patient with the clinical and genotypic diagnosis of the disease. During the prenatal period, the fetus did not have alterations that would suggest the syndrome, but at birth, it had a hemangioma, but without clinical repercussion. In the first three months of life, its development was normal, but from the fourth month on, delays were noticed. At 6 months of age, he was not holding his head, so the parents looked for a geneticist who first made the clinical diagnosis and then requested the karyotype, which confirmed the diagnosis. With this, he already started with multidisciplinary treatment and was still placed to study in regular schools in order to improve his development. Currently, at the age of 15, the patient is in treatment with a multidisciplinary approach and in a school to include children with some neurological weakness in the social environment, in order to avoid bullying from other colleagues. He presents phenotypic alterations characteristic of the syndrome, but the cognitive delay is mild when compared to other adolescents with the same pathology. Therefore, this work shows the need for diagnosis and a multidisciplinary approach in treatment. Even so, more studies are needed to learn more about this syndrome and thus provide a better safeguard of the lives of the patients, as occurred in the case of this patient.

Keywords: Child, Mild intellectual disability, Rubistein-Taybi Syndrome. RESUMO

A síndrome de Rubisntein-Taybi é de origem genética, causada por uma mutação no gene CREBBP, que sofre alterações fenotípicas clássicas e mudanças no desenvolvimento neuropsicomotor. Neste sentido, este artigo visa relatar o caso de um paciente peruano com o diagnóstico clínico e genotípico da doença. Durante o período pré-natal, o feto não teve alterações que sugerissem a síndrome, mas ao nascer, teve um hemangioma, mas sem repercussão clínica. Nos primeiros três meses de vida, seu desenvolvimento foi normal, mas a partir do quarto mês, foram notados atrasos. Aos 6 meses de idade, ele não estava segurando a cabeça, então os pais procuraram um geneticista que primeiro fez o diagnóstico clínico e depois solicitou o cariótipo, o que confirmou o diagnóstico. Com isso, ele já começou com um tratamento multidisciplinar e ainda foi colocado para estudar em escolas regulares, a fim de melhorar seu desenvolvimento. Atualmente, aos 15 anos de idade, o paciente está em tratamento com uma abordagem multidisciplinar e em uma escola para incluir crianças com alguma fraqueza neurológica no ambiente social, a fim de evitar o bullying de outros colegas. Ele apresenta alterações fenotípicas características da síndrome, mas o atraso cognitivo é leve quando comparado a outros adolescentes com a mesma patologia. Portanto, este trabalho mostra a

(3)

necessidade de um diagnóstico e de uma abordagem multidisciplinar no tratamento. Mesmo assim, são necessários mais estudos para aprender mais sobre esta síndrome e assim proporcionar uma melhor salvaguarda da vida dos pacientes, como ocorreu no caso deste paciente.

Palvras-chave: Criança, Deficiência intelectual leve, Síndrome de Rubistein-Taybi. 1 INTRODUCTION

Described in 1963, Rubinstein-Taybi Syndrome (RTS) affects 1 in every 300,000 live births in the general population and 1 in every 300 children born with mental retardation. 1,2_However,

RTS is less frequent in the black race and has no predilection for sex. 3-5

Children who are carriers of this syndrome may present different phenotypes that are classified as classic, light and very serious.

The classical phenotype, caused by alterations in the cyclic-AMP-regulated enhancer binding protein gene (CREBBP), presents primarily the triad of intellectual deficiency, large and wide thumbs, and craniofacial dimorphism, the latter being characterized by findings such as: microcephaly, strabismus, morphological alterations of the teeth, wide nose, arched eyebrows, nasal pyramid with high back, micrognathia, among others possible. 6 In addition, it is possible to find children with short stature, cardiovascular and renal problems, and increased risk of neoplasia. 7

The light phenotype, unlike the classical one, does not suffer from intellectual disability and systemic changes, however, it is characterized by slight craniofacial dimorphism and large and wide thumbs. 8 This phenotype is caused by missense mutations of the CREBBP gene, however, it is commonly known as incomplete RTS. 9

In addition the very severe phenotype has genotypically the contiguous deletion of the chromosome 16p13.3, often fatal. The different clinical characteristics it presents are: severe mental retardation, severe neonatal convulsions, multifocal arrhythmias, cardiac hypoplasia, and severe diseases with risk of death. 10

Little is known yet about the exact causes that lead to these mutations. However, it is already known that it is an autosomal dominant inheritance caused by a condition of haploinsufficiency of the chromosomal region 16p13.3, which generate loss of function of the CREBBP gene of the CREBLigant Protein (CRB).5,11_{In a few cases described in the literature this genetic mutation was}

related to the E1A binding protein p300 (EP300) located on chromosome 22, this being different from the above, but with similar phenotypic characteristics.11

In this sense, individuals with these alterations can present slow metabolic development, which reflects in weight gain and stature loss. In addition, they may present: microcephaly, facial dimorphism, enlarged thumbs and toes.12 Thus, even if they present a normal neonatal development,

(4)

these alterations are already present in the first months of life. Thus, in adolescence and adulthood, these patients accentuate this phenotypic pattern, which is usually accompanied by complications.13,14

Facial dimorphism is characteristic when presenting: thin low frontal line, single eyebrow with plenty of hair volume, protruding and pointed nose with a columella below its wings, deformed and low ears, arched palate, light micrognathia, pointed teeth and atypical smile.12 The extremities present the first dactyl enlarged and may still have an abnormal curvature of the fifth finger, affecting 99% of patients with the syndrome.

There are more changes in the osteomuscular system, such as: pathological abduction of the thumb, ligamentous laxity in large joints, severe recurrent and prolonged aseptic inflammation of the femoral head.12 In addition, Milani and Cols (2015), it may present abnormalities in the cervical region, such as instability of the first vertebrae - Atlas and Exis - and even fusion of the cervical vertebrae. This may evolve with stenosis of the foramen magnum of the cranial box, causing high cervical lesions. The involvement of spontaneous dissections of the arteries is also described and affects more arteries located above the aortic crocus, and it has been reported that there is a greater occurrence of anterior cerebral artery aneurysms compared to patients of the same age who do not have the syndrome. ¹²

These patients may also have ophthalmologic, cardiologic, nephro-urological changes (mainly cryptorchidia) 12-14 and are more likely to have tumors, both benign and malignant, in different parts of the body - from the Central Nervous System to the reproductive system

Knowing this, the diagnosis should be made preferably in the neonatal period, with the union of clinical parameters and complementary tests (laboratory and imaging) that justify the patient's condition. 14 Among all tests, the most important is genetic evaluation.13 Among the various methods, the karyotype analysis is an important test, because it can show rare cytogenetically visible abnormalities and thus verify rearrangements. The FISH technique, when requested, can identify microdeletions, with a detection rate of 5 to 10%. And also are possible to request molecular assay, such as qRT-PCR, multiplex binding dependent probe amplification (MLPA) and chromosomal microarray.12

A point worth mentioning are the differential diagnoses, which are essentially made with other syndromes with low stature and facial dysmorphia that may seem similar, such as: S. Cornelia de Lange and S. Floating-Har-bor. In addition, these diagnoses can be made with syndromes with thumbs and broad hallux, such as: S. Pfeiffer, S. Apert, S. Saethre-Chotzen and S. Greig. What will depend is on the patient's clinic at this time, not on his karyotype. 14

(5)

In order to minimize the damage caused by this anomaly, the treatment should be optimized in adolescence for the known differences in some problems (ophthalmologic characteristics, tendency to weight gain and mood disorders in particular); Audiological evaluation: Performed by an otorhinolaryngologist regardless of the date of diagnosis, with follow-up every 6 months; Ophthalmological evaluation: Carried out at the time of diagnosis, with follow-up every 6 months; Cardiological evaluation: Carried out at the time of diagnosis and during adolescence; Blood pressure evaluation: Carried out during adolescence; Renal ultrasound: Carried out at the time of diagnosis and during adolescence; Orthodontic evaluation: Carried out from 1 year of age with follow-up every 6 months; Endocrinological evaluation: Carried out at the time of diagnosis. If intrauterine, continue at 30 months of age and adolescence; Dermatological evaluation: Performed at the time of diagnosis and adolescence; Genetic counseling: Performed at the time of diagnosis and adolescence. ¹²

In this context, the objective of this article is to report the case of a male patient, in which phenotypically presents differences in relation to what is classically described in the literature and thus enable the discussion and promotion of research on this disease.

2 CASE REPORT

J.S.O.V, male, 15 years old, born and raised in Huancayo - Peru. Born to term, normal delivery, birth weight 3620g, height 50 cm, cephalic perimeter 35cm, apgar 6/7. He had a mechanical aspiration syndrome associated to an umbilical cord wrapped around his neck on the day of birth, which required an emergency cesarean section, so he was admitted to the Intensive Care Unit for thirteen days, being discharged from hospital without complications. It is worth mentioning that all the prenatal follow-up was done and no alterations had been visualized. Moreover, he was born with a hemangioma in the frontal region, superior to glabella, which disappeared alone at 1 year of age. The pediatrician who did the follow-up suspected that this could be related to the condition and that it would be linked to future neurological problems, but nothing was proven.

Until the age of three months the father reports normal growth and development. Only at six months he did not sit or have the cephalic support. At 8 months he could not babble words and currently has speech difficulty, besides having difficulty crawling and starting walking. This was done independently at the age of three.

With all this picture, he was taken to Lima-Peru, in the reference hospital and when consulting with a geneticist she diagnosed him with Rubistein-Taybi Syndrome both clinically

(6)

(typical species, hand with enlarged thumb, anal sounds in the speech attempt) and genetically (karyotype). Even with this early diagnosis and the beginning of treatment, clinical repercussions are still present: deficit in school learning, showing that currently he can count from 1 to 20 and write his name, but the school grades are maximum. This is justified by the presence of mild mental retardation and the anatomical differences in the hands due to the syndrome, writing becomes more difficult. It is worth mentioning that he studies in a school for children with some special need, but that aims at social inclusion.

Partial control of the sphincters was only taken at 6 years of age, but he still has a urinary urgency, no use of diapers and a normal intestinal cold for him.

Because his breathing is primarily oral, he presents recurrent upper airway infections (about 10 to 15 occurrences per year), being resistant to conventional antibiotic therapy and also, when in early childhood, presented otitis averages of repetition, about 4 to 5 per year, which currently no longer presents. What we have is auditory hypersensitivity.

Moreover, it presents hyperopia in the use of corrective lenses, which at 7 years was 13 degrees, but currently is 3.5 degrees, whose reason for regression without any surgical intervention there is no explanation.

Regarding the psychological part, the family reports constant irritability and an alimentary compulsion from early childhood, but without treatment with medication, only educational measures guided by a child psychiatrist. In addition, at the age of seven he underwent surgery for correction of cryptorchidia and at the age of fourteen he underwent surgery for lengthening of the calcaneal tendons, due to his bilateral equine foot.

With the arrival of their puberty and adolescence, parents noticed actions such as attempts at masturbation and rubbing themselves on people with a certain frequency, in addition to increased pubic hair and growth of the genital organ. Due to these habits, he started psychological treatment and remained from 10 to 13 years old, which showed a beneficial effect, but it does not continue because the psychologist has stopped attending and he does not adapt to other professionals. This whole picture shows that the sexual part is with normal development.

In addition to all the medical monitoring of pediatricians, neuropediatricians and psychologists, in Lima and Huancayo, the family has always stimulated him to do physical therapies that stimulated him both physically and psychically. These began at 2 years and 10 months and are perpetuated until the present day. The family believes that independence from individual activities such as bathing, eating alone or expressing what they want are thanks in large part to these

(7)

interventions, in addition to his mental retardation being mild. There are no cases in the family of genetic alterations, even he has a healthy brother.

Physical examination: hypotrophic musculature (4/5+) with preserved strength. Spasticity in lower limbs and normal tone in upper limbs. Increased normal and deep superficial reflexes in lower limbs. Reduced sensitivity to pain in lower limbs. BMI: 26.81 kg/m².

3 DISCUSSION

The patient in question fell into the classic phenotype of Rubinstein-Taybi syndrome (SRT) because of the characteristics presented as typical facies having the characteristic shape of the high and elongated nasal pyramid associated with hypoplasia of the maxilla. In addition, there are changes in thumbs, also present in 99% of patients with this syndrome. 15

With respect to intellectual disability, mental retardation, motor and social deficits, these are present in the patient in question as well as in most cases of SRT. 16

Learning disabilities and behavioural changes should be constantly assessed and school support established. 17

As a normal characteristic of these patients, development and growth at the beginning of life were normal, being noticed by the parents alterations from the third month of life. 14_{These changes}

were observed in the form of neuropsychomotor developmental retardation, such as not being able to sustain the head or to sit. At eight months of age, he was unable to babble words, delayed crawling, and speech difficulty, which has been observed to date. At 6 years of age he still did not have complete sphincter control and currently he presents mictional urgency. Today, he is able to count from 1 to 20 and has learning difficulty due to both intellectual deficit and morphological changes in his hands that imply a greater challenge for writing and learning. 1,6,12

Food compulsion and irritability are phenotypic traits of the patient, as well as can be related to the patient's age range. However, individuals with SRT may in adolescence observe the appearance of nervousness, anxiety, stubbornness, aggressiveness, malaise and irritability. 18-21

The craniofacial changes presented are factors of paramount importance in mouth breathing that these patients may develop, as well as the upper airway infections (UAV) reported in the aforementioned case. 12-14 These can evolve into deafness, which explains the need for annual hearing screening. 22 However, repeated otitis medias and auditory hypersensitivity are possible changes. 14,23,24

(8)

However, SAV infections are linked to craniofacial changes, but these can also result from a humoral response deficit. 23,24 Therefore the treatment of primary immunodeficiency is of paramount importance.

The SRT can also cause ophthalmological alterations, developed by this patient in the form of hyperopia, which today presents a significant improvement without medical explanation. 12-14

Sexual development was normal, pubic hair formation and increase of genital organ, even irritability (characteristic of this age group), however, due to the intellectual deficit there were behaviors socially unacceptable as masturbation and rubbing in people. 12 However, the fact of psychological follow-up brought behavioral improvement, according to the parents. In addition, all the care taken with the neuropsychomotor development, made possible by early diagnosis, was extremely important for the patient's current evolution and independence.

4 FINAL CONSIDERATIONS

The patient with STDs has deficits that affect him globally, which makes him/her need multiprofessional follow-up in order to have an improvement of the clinical picture presented, being this exemplified in the case. In addition to what was demonstrated the early need for insertion of the child in educational institutions, which corroborates cognitive improvement and reduces possible neurocognitive delays that he may have.

Therefore, it is concluded that there is a need for more studies on this syndrome and the promotion of more research in order to treat patients with suspicion and/or with the right diagnosis earlier, with the purpose of reducing future sequelae and increasing the quality of life.

(9)

REFERENCES

1- Rubinstein JH, Taybi H. BroadThumsand toes and facial abnormalities. A possible mental retardationsyndrome. Am J DisChild 1963;105:88-108.

2- Berry AC. Rubinstein-TaybiSyndrome. American Journalof Medical Genetics1987;24:526- 66.

3- Rubinstein JH. Broadthumb-hallux (Rubinstein-Taybi) Syndrome. American Journalof Medical Genetics1990; 6:3-16.

4- Ghanen Q, Dawod S. Monozygotictwinconcordant for RubinsteinTaybisy syndrome. ClinGenet1990;37:429-34.

5- O. Bartsch, W. Kress, O. Kempf, S. Lechno, T. Haaf, and U. Zechner, “Inheritanceandvariableexpression in Rubinstein-Taybisyndrome,” American Journalof Medical GeneticsPart A, vol. 152A, no. 9, pp. 2254–2261, 2010.

6- Allason JE. Rubinstein-TaybiSyndrome: The changing face. American Journalof Medical Genetics1990; [Suppl]6:38-41.

7- M. M. Al-Qattan, A. Jarman, A. Rafique, Z. N. Al-Hassnan, and H. M. Al-Qattan, “Rubinstein-Taybisyndrome in a Saudi boy withdistinctfeaturesandvariants in boththe CREBBP and EP300 genes: a case report,” BMC Medical Genetics, vol. 20, no. 1, p. 12, 2019.

8- O. Bartsch, S. Schmidt, M. Richter et al., “DNA sequencingof CREBBP demonstratesmutations in 56% ofpatientswith Rubinstein-Taybisyndrome (RSTS) and in anotherpatientwithincomplete RSTS,” Hum Genet, vol. 117, no. 5, pp. 485–493, 2005.

9- O. Bartsch, K. Locher, P. Meineckeet al., “Molecular studies in 10 cases of Rubinstein-Taybisyndrome, including a mildvariantshowing a missensemutation in codon 1175 of CREBBP,” Journalof Medical Genetics, vol. 39, no. 7, pp. 496–501,

2002.

10- O. Bartsch, S. Rasi, A. Delicado et al., “Evidence for a new contiguous gene syndrome, thechromosome 16p13.3 deletionsyndrome alias severe Rubinstein- Taybisyndrome,” HumanGenetics, vol. 120, no. 2, pp. 179–186, 2006.

11- MARECOS, Clara; CUNHA, Manuel; CARREIRO, Helena. Rubinstein-Taybi Syndrome: new mutation. Revista Clínica do Hospital Prof. Doutor Fernando Fonseca, v. 2, p. 25-28, 2014.

12- MILANI, Donatella; MANZONI, Francesca; PEZZANI, Lidia; AJMONE, Paola; GERVASINI, Cristina; MENNI, Francesca; ESPOSITO, Susanna. Rubinstein-Taybi syndrome: clinical features, genetic basis, diagnosis, and management. : clinical features, genetic basis, diagnosis, and management. Italian Journal Of Pediatrics, [s.l.], v. 41, n. 1, 2015. Springer Science and Business Media LLC. http://dx.doi.org/10.1186/s13052-015-0110-1.

(10)

13- OLIVEIRA, Carlos Rogério Degrandi; ELIAS, Luciana. Anesthesia in a patient with Rubinstein-Taybi syndrome: case report. Revista Brasileira de Anestesiologia, v. 55, n. 5, p. 546-551, 2005.

14- PINTO-BASTO, J. et al. Genes, children and pediatricians: Rubinstein-Taybi Syndrome. Born and Growing, n. 15 (1), p. 45-48, 2006.

15- Cantani A, Gagliesi D. Rubinstein-Taybi syndrome. Review of 732 cases and analysis of the typical traits. Eur Rev Med Pharmacol Sci. 1998; 2: 81-7

16- Hennekam RC. Rubinstein-Taybi syndrome. Eur J Hum Genet. 2006; 14, 981-85

17- Kumar S, Suthar R, Panigrahi I, Marwaha R. Rubinstein Taybi Syndrome: clinical profile of 11 patients and review of literature. Indian J Hum Genet. 2012; 18: 161–6.

18- Yagihashi T, Kosaki K, Okamoto N, Mizuno S, Kurosawa K, Takahashi T, et al. Age-dependent change in behavioral feature in Rubinstein-Taybi syndrome. Congenit Anom. 2012; 52: 82-6.

19- Levitas AS, Reid CS. 1998. Rubinstein-Taybi syndrome and psychiatric disorders. J Intellect Disabil Res 42:(Pt 4): 284–292.

20- Verhoeven WM, Tuinier S, Kuijpers HJ, Egger JI, Brunner HG. 2010. Psychiatric profile in rubinstein-taybi syndrome. A review and case report. Psychopathology 43:63–68.

21- Hellings JA, Hossain S, Martin JK, Baratang RR. 2002. Psychopathology, GABA, and the Rubinstein-Taybi syndrome: a review and case study. Am J Med Genet 114:190–195.

22- Wiley S, Swayne S, Rubinstein JH, Lanphear NE, Stevens CA. Rubinstein-Taybi Syndrome Medical Guidelines. American Journal of Medical Genetics A. 2003; 119A: 101–10.

23- Naimi DR, Munoz J, Rubinstein J, Hostoffer RW Jr. Rubinstein-Taybi syndrome: an immune deficiency as a cause for recurrent infections. Allergy Asthma Proc. 2006; 27: 281-4.

24- Torres LC, Sugayama SM, Arslanian C, Sales MM, Carneiro-Sampaio M. Evaluation of the immune humoral response of Brazilian patients with Rubinstein-Taybi syndrome. Braz J Med Biol Res. 2010; 43: 1215-24Hellings JA, Hossain S, Martin JK, Baratang RR. 2002. Psychopathology, GABA, and the Rubinstein-Taybi syndrome: a review and case study. Am J Med Genet 114:190– 195.