Misdiagnosed Branchio-Oto-Renal syndrome presenting as proteinuria and renal insufficiency with insidious signs since early childhood: a report of three cases.

BACKGROUND: Branchio-oto-renal (BOR) syndrome is an inherited multi-systemic disorder. Auricular and branchial signs are highly suggestive of BOR syndrome but often develop insidiously, leading to a remarkable misdiagnosis rate. Unlike severe morphological abnormalities of kidneys, knowledge of glomerular involvement in BOR syndrome were limited. CASE PRESENTATION: Three cases, aged 8 ~ 9 years, visited pediatric nephrology department mainly for proteinuria and renal insufficiency, with 24-h proteinuria of 23.8 ~ 68.9 mg/kg and estimated glomerular filtration rate of 8.9 ~ 36.0 mL/min/1.73m2. Moderate-to-severe albuminuria was detected in case 1, while mixed proteinuria was detected in case 2 and 3. Insidious auricular and branchial fistulas were noticed, all developing since early childhood but being neglected previously. EYA1 variants were confirmed by genetic testing in all cases. Delay in diagnosis was 8 ~ 9 years since extra-renal appearances, and 0 ~ 6 years since renal abnormalities. In case 1, therapy of glucocorticoid and immunosuppressive agents to accompanying immune-complex mediated glomerulonephritis was unsatisfying. CONCLUSIONS: BOR syndrome is a rare cause of proteinuria and abnormal kidney function and easily missed, thus requiring more awareness. Careful medical history taking and physical examination are essential to early diagnosis. Massive proteinuria was occasionally seen in BOR syndrome, which might be related to immune complex deposits. A novel pathogenic variant (NM_000503.6 (EYA1): c.1171delT p.Ser391fs*9) was firstly reported.

An infant with congenital heart defects and proteinuria: a case report.

BACKGROUND: Branchio-Oto-Renal (BOR) Syndrome is a rare autosomal disorder with a wide variety of clinical manifestations and a high degree of heterogeneity. Typical clinical manifestations of BOR syndrome include deafness, preauricular fistula, abnormal gill slits, and renal malformations. However, atypical phenotypes such as congenital hip dysplasia, congenital heart anomaly or facial nerve paresis are rare in BOR syndrome, and this might be easily misdiagnosed with other congenital disorders. CASE PRESENTATION: We report a 5-month-old boy of BOR syndrome with "congenital heart defects and proteinuria" as clinical features. Initially, as this case mainly presented with symptoms of recurrent respiratory infections and was found to be with congenital heart disease and proteinuria at the local hospital, but he only was diagnosed with congenital heart disease combined with pulmonary infection and anti-infective and supportive treatment was given. Subsequently, during the physical examination at our hospital, left side preauricular pit and branchial fistulae on the right neck were found. Subsequent evaluation of auditory brainstem response and distortion product otoacoustic emission were revealed sensorineural hearing impairment. Results of renal ultrasonography showed small kidneys. Genetic analysis revealed a microdeletion at chromosome 8q13.2-q13.3 encompassing EYA1 gene, this patient was finally diagnosed with BOR syndrome. Then, this patient received transcatheter patent ductus arteriosus closure and hearing aid treatment. Proteinuria, renal function and hearing ability are monitoring by nephrologist and otologist. The patient is currently being followed up until 3 months after discharge and his condition is stable. CONCLUSION: Careful physical examination, detailed history and the implementation of diagnostic laboratory tests can reduce the incidence of misdiagnosis. Genetic sequencing analysis of patients is a key guide to the differential diagnosis of BOR syndrome.

A Perihilar Variant of Focal Segmental Glomerulosclerosis Due to De novo Branchio-oto-renal Syndrome.

Branchio-oto-renal syndrome is an autosomal dominant disorder characterized by branchial anomalies, hearing loss, and renal urinary tract malformations. We herein report a 32-year-old Japanese man with a right preauricular pit, bilateral mixed hearing loss, and malposition of the right kidney who presented with proteinuria. The findings of a left kidney biopsy were compatible with a perihilar variant of secondary focal segmental glomerular sclerosis. A trio exome analysis conducted among the patient and his parents failed to identify the causal gene variant, despite a sporadic pattern. His kidney function remained stable for 11 years with an angiotensin II receptor blocker.

Molecular Insights Into the Causes of Human Thymic Hypoplasia With Animal Models.

22q11.2 deletion syndrome (DiGeorge), CHARGE syndrome, Nude/SCID and otofaciocervical syndrome type 2 (OTFCS2) are distinct clinical conditions in humans that can result in hypoplasia and occasionally, aplasia of the thymus. Thymic hypoplasia/aplasia is first suggested by absence or significantly reduced numbers of recent thymic emigrants, revealed in standard-of-care newborn screens for T cell receptor excision circles (TRECs). Subsequent clinical assessments will often indicate whether genetic mutations are causal to the low T cell output from the thymus. However, the molecular mechanisms leading to the thymic hypoplasia/aplasia in diverse human syndromes are not fully understood, partly because the problems of the thymus originate during embryogenesis. Rodent and Zebrafish models of these clinical syndromes have been used to better define the underlying basis of the clinical presentations. Results from these animal models are uncovering contributions of different cell types in the specification, differentiation, and expansion of the thymus. Cell populations such as epithelial cells, mesenchymal cells, endothelial cells, and thymocytes are variably affected depending on the human syndrome responsible for the thymic hypoplasia. In the current review, findings from the diverse animal models will be described in relation to the clinical phenotypes. Importantly, these results are suggesting new strategies for regenerating thymic tissue in patients with distinct congenital disorders.

EYA1 mutations leads to Branchio-Oto syndrome in two Chinese Han deaf families.

OBJECTIVES: Branchio-Oto (BO) syndrome is one of the common syndromic forms of hearing loss. In this study, we aimed to characterize the clinical and genetic features of BO syndrome in two Chinese Han deaf families. METHODS: The auditory and other BO-related clinical features of Family 1809 and Family 1974 were summarized. Targeted next-generation sequencing in 144 known deafness genes was performed in the probands. Co-segregation of the pathogenic mutations and the phenotype was confirmed by Sanger sequencing in the family members. RESULTS: Interfamilial and intrafamilial variations can be observed in the clinical phenotypes of BO syndrome in Family 1809 and 1974. A novel c.1493_1494insAT (p.Ile498PhefsTer*3) mutation and a previous reported c.967-2A>G mutation in EYA1 were identified as the pathogenic cause in Family 1974 and 1809, respectively. CONCLUSION: Our results supported the heterogeneity of the genetic and phenotypic spectrum of BO syndrome. The recurrent c.967-2A>G in different ethnical groups suggested that it is a hot-spot mutation.

Whole exome sequencing identifies a mutation in EYA1 and GLI3 in a patient with branchio­otic syndrome and esophageal atresia: Coincidence or a digenic mode of inheritance?

Branchio­otic (BO) syndrome is a clinically and genetically heterogeneous disorder that presents with variable branchial arch and otic anomalies. Dominant mutations in the human homologues of the Drosophila eyes absent (EYA1) gene, and the Drosophila sine oculis homeobox 1 and 5 (SIX1 and SIX5, respectively) genes have been causally associated with BO syndrome. Esophageal atresia (EA), with or without tracheo­esophageal fistula (TEF), is the most common type of malformation of the upper digestive tract. To date, its causes are poorly understood. The present study investigated a family with three affected members who all presented with classic BO associated symptoms. Notably, the index patient also presented with the most common EA/TEF subtype type 3b. Whole exome sequencing (WES) was performed in the index patient, and prioritized genetic variants and their segregation in the family were analyzed by Sanger sequencing. WES demonstrated a known disease­causing heterozygous EYA1 splice variant in the patient, as well as his sister and mother; all of whom were affected with BO syndrome. A further GLI family zinc finger 3 (GLI3) splice variant of unknown significance, inherited from the unaffected father, was also detected in the index patient. EYA1 and GLI3 are involved in the Sonic Hedgehog transcriptional network and GLI3 seems to be involved in human foregut malformations. Therefore, one may hypothesize a digenic inheritance model involving EYA1 and GLI3, where the effect of the GLI3 variant observed here only emerges in the background of the EYA1 defect.

The Pantheon Variant of the Classic Cathedral Dome Procedure for Parieto-Occipital Skull Deformities.

OBJECTIVE: To describe a new technique for the reconstruction of parieto-occipital skull deformities. METHODS AND RESULTS: The technique is a variant of the previously described "cathedral dome procedure" used for frontal skull deformities. The authors apply the same principle of remodeling by making meridional slat craniotomies surrounding the depressed dome of the posterior skull deformity, followed by "green-stick fracture-reshaping" of the meridional slats to elevate and support the excised depressed dome. The authors present an illustrative patient with a follow-up of 2 years and an excellent cosmetic result. CONCLUSION: The authors introduce a new operative technique for the reconstruction of parieto-occipital skull deformities with excellent long-term results. The freshly reconstructed occiput resembles the dome of the pantheon in Rome, Italy, whose unique features inspired us to name this procedure the "Pantheon" variant of the cathedral dome operation.

Hearing-impaired young people - a physician's guide .

Physicians reading this will have a broad range of in-depth knowledge about their own subspecialty. However, in daily medical practice there are topics of which all physicians should have some knowledge. Those who deal with young people should have some knowledge of the needs of the hearing-impaired population within this group of patients. This article is intended to provide an overview of young people with hearing impairment (HIYP), the challenges they face and what we can do to help them. In this paper, we assume that data published regarding hearing-impaired children apply to HIYP from 13 years (the age at which the transition process begins) to 25 years of age (the age at which 'youth' according to the World health Organization and the Education Health Care Plan ends).

Branchio-oto-renal syndrome presenting with syndrome of hyporeninemic hypoaldosteronism.

Branchio-oto-renal (BOR) syndrome is an autosomal dominant, clinically heterogeneous disorder characterized by branchial arch anomalies, hearing impairment, and renal malformations. We report the case of a 10-year-old boy with BOR syndrome who presented with hyperkalemic hyperchloremic metabolic acidosis due to hyporeninemic hypoaldosteronism. The child also had mental retardation and spastic diplegia which have hitherto not been described in BOR syndrome.

A novel PAX1 null homozygous mutation in autosomal recessive otofaciocervical syndrome associated with severe combined immunodeficiency.

Otofaciocervical syndrome (OFCS) is a rare disorder characterized by facial anomalies, cup-shaped low-set ears, preauricular fistulas, hearing loss, branchial defects, skeletal anomalies, and mild intellectual disability. Autosomal dominant cases are caused by deletions or point mutations of EYA1. A single family with an autosomal recessive form of OFCS and a homozygous missense mutation in PAX1 gene has been described. We report whole exome sequencing of 4 members of a consanguineous family in which 2 children, showing features of OFCS, expired from severe combined immunodeficiency (SCID). To date, the co-occurrence of OFCS and SCID has never been reported. We found a nonsense homozygous mutation in PAX1 gene in the 2 affected children. In mice, Pax1 is required for the formation of specific skeletal structures as well as for the development of a fully functional thymus. The mouse model strongly supports the hypothesis that PAX1 depletion in our patients caused thymus aplasia responsible for SCID. This report provides evidence that bi-allelic null PAX1 mutations may lead to a multi-system autosomal recessive disorders, where SCID might represent the main feature.

Does canal wall down mastoidectomy benefit syndromic children with congenital aural stenosis?

OBJECTIVES: To determine whether a canal wall down mastoidectomy can provide long-term benefit for children with aural stenosis. METHODS: Retrospective case series of children with congenital aural stenosis having undergone a canal wall down mastoidectomy over a twelve-year period at a tertiary children's hospital. RESULTS: Data from thirteen children who underwent a total of twenty canal wall down mastoidectomies for aural stenosis were reviewed. The mean age at surgery was 7.1 years (range, 3.3-12.3 years). All patients had genetic syndromes including Trisomy 21 (n = 7), Trisomy 21 and Pierre Robin sequence (n = 1), Angelmann (n = 1), Cri-du-chat (n = 1), Branchio-oto-renal syndrome (n = 1), Spina bifida (n = 1) and Nager syndrome (n = 1). Seven (54%) children underwent bilateral canal wall down mastoidectomies. All thirteen ears that could not be visualized preoperatively had improved ease of office examination following surgery. Only one patient required revision surgery and all canals were patent at the last clinic visit. The mean follow-up was 4.9 years. There were no cases of facial nerve injury or cerebrospinal fluid leak. CONCLUSION: Syndromic children with congenital aural stenosis with poorly pneumatized mastoids may benefit from canal wall down mastoidectomy to improve ease of office examinations.

Otofaciocervical syndrome and metachondromatosis in a girl: Presentation of a novel association and remarks on clinical variability of branchial-arch disorders.

Otofaciocervical syndrome (OFCS) is a rare disorder characterized by facial, ear, branchial, and musculoskeletal anomalies, along with hearing loss and mild intellectual disability. Clinically, its distinction from branchiootorenal syndrome can be difficult. To date, the coexistence of OFCS and metachondromatosis has not been reported. Here, we describe a sporadic patient with both OFCS and metachondromatosis. This novel association prompts us to do some remarks on the clinical variability of branchial-arch disorders; in fact, our observations are consistent with the highly variable expressivity of OFCS and illustrate the need of a more accurate characterization of these branchial-arch disorders. In the meantime, involvement of clavicles, scapulae and shoulders remains a distinctive feature of OFCS.

Novel partial duplication of EYA1 causes branchiootic syndrome in a large Brazilian family.

OBJECTIVE: To identify novel genetic causes of syndromic hearing loss in Brazil. DESIGN: To map a candidate chromosomal region through linkage studies in an extensive Brazilian family and identify novel pathogenic variants using sequencing and array-CGH. STUDY SAMPLE: Brazilian pedigree with individuals affected by BO syndrome characterized by deafness and malformations of outer, middle and inner ear, auricular and cervical fistulae, but no renal abnormalities. RESULTS: Whole genome microarray-SNP scanning on samples of 11 affected individuals detected a multipoint Lod score of 2.6 in the EYA1 gene region (chromosome 8). Sequencing of EYA1 in affected patients did not reveal pathogenic mutations. However, oligonucleotide-array-CGH detected a duplication of 71.8Kb involving exons 4 to 10 of EYA1 (heterozygous state). Real-time-PCR confirmed the duplication in fourteen of fifteen affected individuals and absence in 13 unaffected individuals. The exception involved a consanguineous parentage and was assumed to involve a different genetic mechanism. CONCLUSIONS: Our findings implicate this EYA1 partial duplication segregating with BO phenotype in a Brazilian pedigree and is the first description of a large duplication leading to the BOR/BO syndrome.

Aneurysmal dilatation associated with arteriovenous fistula in a transplanted kidney after renal biopsies.

AVF is a known complication of renal biopsy in both native and transplanted kidneys. A 20-yr-old woman with bilateral hypoplastic kidneys due to branchio-oto-renal syndrome had received living-donor renal transplantation from her father at the age of 11. She had undergone allograft renal biopsies six times and all puncture sites were at the lower pole of her kidney from the first to the fifth biopsy. AVF with aneurysmal dilation (30 mm) had developed at the puncture site after the fifth biopsy. TAE was successfully performed with 11 platinum coils in the branch of the renal artery feeding the aneurysm. According to a review of the literature, the incidence of AVF is higher in transplanted kidneys than in native kidneys (7.5% vs. 2.1%) because transplanted kidneys, as single kidneys, are likely to be punctured repeatedly at the same site. When renal biopsy of a transplanted kidney is performed, previous biopsy puncture sites should be considered and the biopsy should be performed at a different site, if possible, to prevent the development of AVF.

A true branchial fistula in the context of branchiootic syndrome: challenges of diagnosis and management.

BACKGROUND: The presence of a branchial fistula with communication both internally and externally: a 'true' branchial fistula is rare, and may arise in the context of autosomal dominant conditions such as branchiootic syndrome and branchiootorenal syndrome. STUDY: We discuss the case of a true branchial fistula, which recurred after initial surgical excision, in a patient with branchiootic syndrome. The residual tract was dissected in a second operation through stepladder neck incisions and removed in toto via an intraoral approach. No renal abnormalities were detected on investigation with ultrasound. DISCUSSION: Incomplete excision of a branchial sinus is likely to cause recurrence however intraoperative visualisation of the tract can can sometimes prove challenging. An combined intraoral and external approach aids delineation and tract definition when there is a true branchial fistula and can therefore facilitate a complete excision. Suspicion of an hereditary aetiology should be raised in patients with bilateral or preauricular features, or a positive family history, which may then prompt additional renal and genetic investigation.

Combined hamartoma of the retina and retinal pigment epithelium in branchio-otic syndrome.

A 15-month-old boy with established branchio-otic syndrome was evaluated for decreased red reflex in the left eye. Fundus examination of left eye revealed a gray epiretinal membrane with retinal traction and ill-defined macular thickening, found on ultrasonography as a dense flat region 1.7 mm in thickness. Enhanced depth imaging optical coherence tomography revealed an epiretinal membrane with macular thickening, retinal folding, and full-thickness retinal disorganization, consistent with combined hamartoma of the retina and retinal pigment epithelium. Over 5 years of follow-up, the branchio-otic syndrome was unchanged and the combined hamartoma remained stable.

Coexisting first and bilateral second branchial fistulas in a child with nonfamilial branchio-otic syndrome.

We describe what we believe is only the third reported case of coexisting first and bilateral second branchial fistulas associated with nonfamilial branchio-otic syndrome. The patient was a 6-year-old girl who presented with bilaterally draining anterior neck puncta, a preauricular sinus, and moderately severe bilateral hearing loss. She had no family history of branchial anomalies. Compared with branchial cysts and sinuses, branchial fistulas are rare. Even more rare are bilateral second branchial fistulas coexisting with first branchial anomalies, as only 10 cases have been previously reported in the English-language literature. Of these 10 cases, 5 were associated with either branchio-otic syndrome or branchio-oto-renal syndrome; 2 patients had familial branchio-otic syndrome, 2 had nonfamilial branchio-otic syndrome, and 1 had nonfamilial branchio-oto-renal syndrome.