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Bardet-Biedl Syndrome – Case Presentation CASE PRESENTATIONS BARDET-BIEDL SYNDROME – CASE PRESENTATION Sorin Ioan Iurian1,2, Heleen Arts3, Han Brunner3, Dana Fintina2 1“Lucian Blaga” University, Sibiu 2Pediatric Clinic Hospital, Sibiu 3Genetic Department, Radboud University, Nijmegen, The Nederlands ABSTRACT Bardet-Biedl syndrome (autosomal-recessive inheritance) is characterized by obesity, retinal dystrophy, poly- dactyly and mental retardation. The authors emphasize the necessary steps in order to establish the diagnosis for an infant with overweight, polydactyly and hypogenitalism. Keywords: Bardet-Biedl syndrome, obesity (overweight), polydactyly INTRODUCTION drocephalus, polycystic kidney disease, Meckel-Gru- ber syndrome, Joubert syndrome (1). The genetic Bardet-Biedl syndrome (BBS) in a condition background of SBB is heterogeneous, including 15 consisting of multiple anomalies: vision loss, early genes. Even though SBB is autosomal-recessive inhe- onset obesity, polydactyly and mental retardation. rited, in some cases two mutations in one BBS gene th At the end of XIX century, John Laurence and and a third mutation in secondary locus are necessary Robert Moon described four patients with retinitis for BBS phenotype (triallelic inheritance) (2). The 4 pigmentosa, mental retardation, spastic parapare- most commonly involved genes are BBS1, BBS2, sis, short stature and hypogenitalism. In 1920 BBS10 and BBS12, their screening identifying al- George Bardet, based on analysis on hypothalamic most 62% of BBS patiens (3). The BBS12 gene ano- obesity, described a patients group with obesity, malies (vertebrate specifi c gene) is responsible for 6% retinitis pigmentosa and hexadactyly. Then, in of SBB patients. BBS12, BBS6 and BBS10 genes are 1922, Artur Biedl published a study about siblings type II chaperonins and are specifi cally involved in with polydactyly and intellectual impairment. In ciliary functions (4). 1925 it was decided that the disorders described by There are differing disease phenotypes in accor- all four physicians were the same and the disease dance with involved BBS gene (2): was named Laurence-Moon-Bardet-Biedl syn- • BBS patients with BBS2/BBS4 mutations are drome. Recently, this syndrome was split into Lau- signifi cantly shorter than their parents; rence-Moon syndrome characterized by spastic • BBS3 patients have polydactyly (lower paraparesis and mental retardation and Biedl-Bar- limbs), obesity and low IQ; det syndrome (BBS) that implies obesity, polydac- • BBS5 subjects have severe visual impair- tyly and learning diffi culties. ment and brachydactyly/syndactyly, but no polydactyly; Etiology • the BBS6 mutation is also responsible for BBS belongs to ciliopathies, like other disorders: McKusick-Kaufman syndrome, a disorder primary ciliary dyskinesia/ Kartagener syndrome, hy- with surprising phenotypic overlap (5). Corresponding author: Iurian Sorin Ioan, “Lucian Blaga” University, 10 Victorie Boulervard, Sibiu E-mail: [email protected] ROMANIAN JOURNAL OF PEDIATRICS – VOL. LXIV, NO. 3, YEAR 2015 289 290 ROMANIAN JOURNAL OF PEDIATRICS – VOL. LXIV, NO. 3, YEAR 2015 Pathophysiology Treatment There is a complex interaction between genetic There is no specifi c treatment for BBS. factors and ciliary dysfunction. In context of The prognosis is poor when renal failure occurs. severe impairment of tubule cilia function, renal Prophylactic measures. The genetic counseling failure will be a leading cause of mortality in and preconception genotyping of genitors are use- BBS (6). ful. Epidemiology CASE PRESENTATION The disease prevalence in Europe and North America is around 1 in 150,000 newborns. A high C.V.N, 5 month-old male infant, was admitted incidence is reported in Bedouins and Arab popu- in pediatric department for further evaluation and lation of Kuwait (1:13,500). Ratio of male: female treatment in context of breathing diffi culties, is approximately 1.3:1. coughing and nasal obstruction. The BBS patients present following features, Family history: healthy and non- consanguine- ous parents; mother VI Gesta V Para (a miscar- (7): riage); the index case is the 5th child in the family; • obesity (83% of patients); the two brothers and two sisters of infant are • mental retardation (IQ of 79 or below in 77% healthy; one sister (15 years old) presented during of patients); childhood primary teeth anomalies (she changed • limbs anomalies: postaxial polydactyly four times the maxillary central incisors). Obstetric (58%), syndactyly, brachydactyly (50%); history: birth at 9 months gestational age (cephalic • ocular abnormalities: retinal dystrophy (100%), presentation); birth weight 3,800 g; APGAR score myopia (75%), astigmatism (63%), nystagmus = 10/1 minut. (52%), glaucoma (22%), posterior capsular Patient history: three hospitalisations justifi ed cataract (44%), retinitis pigmentosa (8%); by acute bronchiolitis. • cardiac abnormalities: hypertrophy of inter- The clinical exam: abundant adipose tissue, ventricular septum/left ventricle and dilated weight = 10.8 kg (>95th percentile), head circumfer- cardiomyopathy; ence = 41 cm, facial dysmorphism (up-slanted pal- • urinary tract anomalies: abnormal calyces pebral fi ssures, low-inserted hair anteriorly), skin (95%), renal cysts (62%), focal scarring (24%), pallor, bilateral accessory nipples (polithelia), skin ectopic urethra; dryness (xerodermia), seboreic dermatitis of scalp, • genital anomalies: hypogenitalism in males palmar simian crease; short neck, rickets signs, dig- (small penis/testes), uterus duplex, uterus hy- its anomalies (brachydactyly, postaxial polydactyly – poplasia, septate vagina, vaginal atresia; bilateral foot, partial syndactyly affecting toes 5 and • other anomalies: hepatic fi brosis, diabetes 6 on left foot); hypotonia; arm/forearm ratio <1; pu- mellitus, diabetes insipidus, clinodactily of bis to vertex / pubis to fl oor ratio >1; nasal obstruc- the 5th fi nger, hearing loss, hippocampal dys- tion, rhinorrhea, 46 breats/minut, dry coughing, genesis. wheezing, dyspnoea, prolonged expiration, sibilant In evolution, patients can develop neuropsy- crackles, a grade 1/6 systolic murmur, 120 beats/ chiatric symptoms (obsessive-compulsive disor- minut; congestion of pharynx, normal macroscopic der, attention diffi culties), schizophrenia, ataxia, appearance of the urine, hypogenitalism (small pe- renal tubular acidosis, renal failure, hypertension, nis, small testicles); no meningitis signs, delayed bronchial asthma (in 25% of cases). Visual acuity motor skills (according to age of two months). deteriorates with age. Investigations Investigations Blood tests: leukocytes 12.190/mm3 (lympho- The probable diagnosis is established based on cytes 67%, neutrophils 17%, monocytes 13%), clinical features, but its confi rmation requires ge- haemoglobin = 10,6 g/dl; platelets = 395.000/mm3; netic testing to differentiate BBS from other rare C reactive protein = 1 mg/L (normal < 10), hepatic genetic disorders. and renal markers within normal range; normal val- The evaluation of renal and cardiac functions ues for iron, glucose, cholesterol and triglycerides; (blood tests and imagistics) is recommended for alpha 1-antitripsine in reference range. prognosis assessment. Urinalysis was normal. ROMANIAN JOURNAL OF PEDIATRICS – VOL. LXIV, NO. 3, YEAR 2015 291 Iontophoresis test: normal result. childhood), type 2 diabetes mellitus, mental retar- Imagistic assessment: abdominal ultrasound dation, short hands and feet, underdeveloped geni- exam without pathological features; the echocardi- tals, (13); this condition is considered less probable ogram revealed moderate hypertrophy of interven- because of atypical (during infancy) onset of tricular septum and left ventricle, hypertrophic car- overweight. diomyopathy. Ocular fundus exam: no retinal dystrophy. Positive diagnosis Differential diagnosis included: The patient phenotype (overweight, postaxial – Bardet-Biedl syndrome can be considered in polydactyly, partial syndactyly, genital anomalies) this case due to overweight, polydactyly and hypo- correlated with cardiac malformation (hypertrophy of genitalism; interventricular septum and left ventricle) indicated – Laurence-Moon syndrome (LMS); LMS pa- the possibility of BBS, justifying genetic assessment tients are affected by spastic paraparesis, but no (Nijmegen, The Nederlands) including the screening polydactyly, so this disease is considered less prob- of all known genes associated with BBS. The genetic able; evaluation was performed not only for infant, but also – Cohen syndrome is characterized by intellec- for genitors and consisted in “next generation DNA tual disability, microcephaly, hypotonia, joint hy- sequencing”. This revealed a homozygous nonsense permobility, myopia, retinal dystrophy, obesity mutation in BBS12 (c.1063C > T, p.Arg.355). This around the torso with slender arms and legs (onset mutation was fi rst reported to be associated with BBS during adolescence) and face dysmorphism (bul- by Stoetzel et al. in 2007 (4). Both parents are hetero- bous nasal tip, prominent maxillary central inci- zygous carriers for the variant. sors). In context of normal head circumference/ Based on genetic test, the authors considered absence of dysmorphism in conjunction with early BBS diagnosis in an infant with acute bronchiolitis onset obesity, Cohen syndrome was ruled out; and recurrent wheezing. – Alstrom syndrome is a genetic autosomal-re- cessive inherited disease; the illness starts in infan- Treatment cy and consists in short stature, retinal dystrophy The bronchiolitis therapy included
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