Dysplastic Ears Research Articles

A novel SALL1 C757T mutation in a Chinese family causes a rare disease --Townes-Brocks syndrome

BackgroundTownes-Brocks syndrome (TBS) is a rare genetic disorder characterized by imperforate anus, dysplastic ears, thumb malformations, and other abnormalities. Previous studies have revealed that mutations in the SALL1 gene can disrupt normal development, resulting in the characteristic features of Townes-Brocks syndrome. Spalt-like transcription factors (SALLs) are highly conserved proteins that play important roles in various cellular processes, including embryonic development, cell differentiation, and cell survival. Over 400 different variants or mutations have been reported in the SALL1 gene in individuals with TBS. Most of these variants lead to the formation of premature termination codons (PTCs), also known as nonsense mutations. The majority of these PTCs occur in a specific region of the SALL1 gene called the “hotspot region”, which is particularly susceptible to mutation.MethodsIn this study, we conducted whole-exome sequencing on a three-generation Chinese family with anorectal malformations.ResultsWe identified a novel heterozygous mutation (chr16:51175376:c.757 C > T p.Gln253*) in the SALL1 gene. Molecular analysis revealed a heterozygous C to T transition at nucleotide position 757 in exon 2 of the SALL1 (NM_002968) gene. This mutation is predicted to result in the substitution of the Gln253 codon with a premature stop codon (p.Gln253*). The glutamine-rich domain forms a long alpha helix, enabling the mutant protein to interact with the wild-type SALL1 protein. This interaction may result in steric hindrance effects on the wild-type SALL1 protein.ConclusionsOur findings have expanded the mutation database of the SALL1 gene, which is significant for genetic counseling and clinical surveillance in the affected family. Furthermore, our study enhances the understanding of Townes-Brocks syndrome and has the potential to improve its diagnosis and treatment.

Townes-Brocks Syndrome Revealed by Kidney Gene Panel Testing

Townes-Brocks syndrome (TBS), a rare autosomal dominant genetic condition associated with SALL1 (Spalt like Transcription Factor 1), is reported to be present in 1:238,000 individuals in the general population. TBS is characterized by the triad of anorectal malformations, dysplastic ears, with or without hearing impairment, and hand or thumb anomalies. Although kidney involvement is less common in TBS, the disease can progress to kidney failure. Here, we sought to characterize the incidence of SALL1 variants in individuals undergoing broad-based genetic testing with a kidney gene panel and to quantify the presence of (extra)renal features. A retrospective analysis of the genetic data from a 385-gene panel identified cases with a pathogenic (P) or likely pathogenic (LP) variant in SALL1. Data including age, features, and disease progression were collected. Of 35,044 samples, P or LP variants in SALL1 were identified in 22, yielding a prevalence of 1:1592 among patients tested for monogenic kidney disease, and 1:342 among cases identified with a monogenic kidney disease. Among this cohort, the median patient age was 23 years (range: 3 months-62 years) with chronic kidney disease (CKD) reported in 91% (20/22) of cases. Reported kidney features included renal agenesis/hypoplasia (7/22; 32%), focal segmental glomerulosclerosis (4/22; 18%), and kidney cysts (3/22; 14%). Confirmed extrarenal features included hearing loss and/or ear features (7/22; 32%), anorectal malformations (6/22; 27%) and hand or thumb abnormalities (4/22; 18%). Three patients (3/22; 14%) had both a priori TBS diagnoses and the traditional "triad." Traditionally, a molecular diagnosis was ascertained primarily in individuals presenting with cardinal features of TBS; therefore, individuals with mild or atypical presentations were often overlooked clinically. Our findings reveal that SALL1 P/LP variants could be a consequential contributor to monogenic kidney disease.

First and second branchial arch involvement in mandibulofacial dysostosis Guion-Almeida type.

Mandibulofacial dysostosis Guion-Almeida Type (MFDGA; OMIM#610536) is a rare autosomal dominant genetic disorder caused by heterozygous pathogenic variants in the EFTUD2 gene. Mandibulofacial dysostoses are characterised by the core triad malar hypoplasia, maxillary hypoplasia and dysplastic ears, all derived by the impaired development of the first and second branchial arches. Differential diagnosis is often challenging. The early genetic diagnosis is extremely useful, not only for the correct management of cranial malformations, but also for the early diagnosis and treatment of the comorbidities associated to the disease, which greatly benefit from early treatment.

The phenotypic spectrum of terminal 6q deletions based on a large cohort derived from social media and literature: a prominent role for DLL1

BackgroundTerminal 6q deletions are rare, and the number of well-defined published cases is limited. Since parents of children with these aberrations often search the internet and unite via international social media platforms, these dedicated platforms may hold valuable knowledge about additional cases. The Chromosome 6 Project is a collaboration between researchers and clinicians at the University Medical Center Groningen and members of a Chromosome 6 support group on Facebook. The aim of the project is to improve the surveillance of patients with chromosome 6 aberrations and the support for their families by increasing the available information about these rare aberrations. This parent-driven research project makes use of information collected directly from parents via a multilingual online questionnaire. Here, we report our findings on 93 individuals with terminal 6q deletions and 11 individuals with interstitial 6q26q27 deletions, a cohort that includes 38 newly identified individuals.ResultsUsing this cohort, we can identify a common terminal 6q deletion phenotype that includes microcephaly, dysplastic outer ears, hypertelorism, vision problems, abnormal eye movements, dental abnormalities, feeding problems, recurrent infections, respiratory problems, spinal cord abnormalities, abnormal vertebrae, scoliosis, joint hypermobility, brain abnormalities (ventriculomegaly/hydrocephaly, corpus callosum abnormality and cortical dysplasia), seizures, hypotonia, ataxia, torticollis, balance problems, developmental delay, sleeping problems and hyperactivity. Other frequently reported clinical characteristics are congenital heart defects, kidney problems, abnormalities of the female genitalia, spina bifida, anal abnormalities, positional foot deformities, hypertonia and self-harming behaviour. The phenotypes were comparable up to a deletion size of 7.1 Mb, and most features could be attributed to the terminally located gene DLL1. Larger deletions that include QKI (> 7.1 Mb) lead to a more severe phenotype that includes additional clinical characteristics.ConclusionsTerminal 6q deletions cause a common but highly variable phenotype. Most clinical characteristics can be linked to the smallest terminal 6q deletions that include the gene DLL1 (> 500 kb). Based on our findings, we provide recommendations for clinical follow-up and surveillance of individuals with terminal 6q deletions.

Increased Nuchal Translucency Without Aneuploidy in a Fetus: Abnormal Postnatal Radiograph and a Novel Mutation.

Increased Nuchal Translucency Without Aneuploidy in a Fetus: Abnormal Postnatal Radiograph and a Novel Mutation.

Congenital hypopituitarism and multiple midline defects in a newborn with non-familial Cat Eye syndrome

BackgroundCat eye syndrome (CES) is a rare chromosomal disease, with estimated incidence of about 1 in 100,000 live newborns. The classic triad of iris coloboma, anorectal malformations, and auricular abnormalities is present in 40% of patients, and other congenital defects may also be observed. The typical associated cytogenetic anomaly relies on an extra chromosome, derived from an inverted duplication of short arm and proximal long arm of chromosome 22, resulting in partial trisomy or tetrasomy of such regions (inv dup 22pter-22q11.2).Case presentationWe report on a full-term newborn, referred to us soon after birth. Physical examination showed facial dysmorphisms, including hypertelorism, down slanted palpebral fissures, and dysplastic ears with tragus hypoplasia and pre-auricular pit. Ophthalmologic evaluation and heart ultrasound identified left chorioretinal and iris coloboma and ostium secundum type atrial septal defect, respectively. Based on the suspicion of cat eye syndrome, a standard karyotype analysis was performed, and detected an extra small marker chromosome confirming the CES diagnosis. The chromosomal abnormality was then defined by array comparative genome hybridization (a-CGH, performed also in the parents), which identified the size of the rearrangement (3 Mb), and its de novo occurrence. Postnatally, our newborn presented with persistent hypoglycemia and cholestatic jaundice. Endocrine tests revealed congenital hypothyroidism, cortisol and growth hormone (GH) deficiencies, which were treated with replacement therapies (levotiroxine and hydrocortisone). Brain magnetic resonance imaging, later performed, showed aplasia of the anterior pituitary gland, agenesis of the stalk and ectopic neurohypophysis, confirming the congenital hypopituitarism diagnosis. She was discharged at 2 months of age, and included in a multidisciplinary follow-up. She currently is 7 months old and shows a severe global growth failure, and developmental delay. She started GH replacement treatment, and continues oral hydrocortisone, along with ursodeoxycholic acid and levothyroxine, allowing an adequate control of glycemic and thyroid profiles as well as of cholestasis.ConclusionsCES phenotypic spectrum is wide and highly variable. Our report highlights how among the possible associated endocrine disorders, congenital hypopituitarism may occur, leading to persistent hypoglycemia and cholestasis. These patients should be promptly assessed for complete hormonal evaluations, in addition to major malformations and midline anomalies. Early recognition of such defects is necessary to decrease fatal events, as well as short and long-term related adverse outcomes.

Management of Harlequin Ichthyosis: A Brief Review of the Recent Literature.

Harlequin ichthyosis (HI) is a life-threatening genetic disorder that largely affects the skin of infants. HI is the most severe form of the autosomal recessive disorder known as ichthyosis. It is caused by mutations in the A12 cassette (lipid-transporter adenosine triphosphate-binding cassette A12). Neonates affected by this disease are born with specific morphological characteristics, the most prominent of which is the appearance of platelet keratotic scales separated by erythematous fissures. The facial features include eclabium, ectropion, a distinct flattened nose, and dysplastic ears. A common finding among those with HI is impaired skin barrier function. The purpose of the present narrative review is to assess the most recent literature regarding the management of HI. Emphasis is given to surgical management and consultation, to the indications for timing and surgical intervention, to the risks that are presented with surgery, and to the details of the surgical procedure itself. Management of HI requires a multidisciplinary team of experts, and specific guidelines are needed in order for the risks to be minimized and viability to be increased.

EP093: De novo interstitial deletion of chromosome 7p22.1p21.2: A case report

Partial monosomy of the short arm (p) of chromosome 7 is a rare chromosomal disorder associated with a variable phenotype, depending on the size and location of the deleted region. When the deletion involves the interstitial deletion of 7p22.1p21.2 region, literature review describes phenotypic features that include craniosynostosis, microcephaly, ocular hypotelorism or hypertelorism, downslanting palpebral fissures, epicanthal folds, dysplastic ears, depressed nasal bridge, and cleft palate. Abnormalities of the thumbs and feet have been described, and also cardiovascular, renal and genital anomalies.

Clinical and molecular cytogenetic description of a female patient with de novo 18q inversion duplication/deletion

The genetic causes of global developmental delay (GDD) and intellectual disability (ID) are heterogeneous. Chromosomal imbalance has been recognized as the most frequent cause of ID for years. We describe the report of a female patient aged 1 year and 5 months at presentation who had GDD, prenatal growth retardation, failure to thrive, microcephaly, dysmorphic facial features including: broad forehead, high anterior hair line with sparse scalp hair, wide palpebral fissures, long eye lashes, blue sclera, sparse arched eye brows, prominent and wide nasal root, hypertelorism, micrognathia and dysplastic low set ears in addition to widely spaced nipples, bilateral clenched fists, camptodactyly, rocker bottom feet and brittle nails.. Her karyotype revealed 46,XX,add (18)(q23). Comprehensive cytogenomic analysis was performed using multiplex ligation-dependent probe amplification (MLPA), fluorescence in situ hybridization (FISH), and aCGH techniques to determine the parental origin and the possible mechanism responsible for this abnormal karyotype. Both parents had normal karyotypes. MLPA and FISH analysis for the patient revealed deletion of 18q subtelomere, and whole chromosome paint (WCP) associated with inverted DAPI indicated that all the duplicated segments originated from chromosome 18 and there was inversion of 18q segment. Array CGH identified 55.8-Mb duplicated segment and 614-kb deleted terminal 18q. Single nucleotide polymorphism (SNP) analysis for the patient and the parents revealed that the duplicated and deleted 18q regions originated from paternal chromosome 18. These findings suggested that the event occurred during paternal meiosis or early postzygotic stage. The suggested mechanism responsible for this type of rearrangement is nonhomologous end point recombination and U-type exchange.

Nadir bir olgu: Trizomi 8 Mozaisizm Sendromu

Trisomy 8 mosaicism syndrome (T8MS ) is a rare chromosome disorder caused by the presence of a extra chromosome 8 in some cells of the body. T8MS is a clinically variable condition associated with a number of developmental abnormalities. We report a of T8MS with dysmorphic features and congenital anomalies. A 3.5-month-old boy was referred to the genetic department because of his atypical facial appearance. Physical examination revealed microcephaly, hypertelorism, flattened nasal root, deeply located eyes, strabismus, dysplastic ears, cleft palate, deep hand and foot lines, camptodacty and hypotonicity. He had additional anomalies such as hearing loss, peripheral cataract in the left eye, bilateral advanced vesicoureteral reflux, and corpus callosum dysgenesis. Chromosome analysis revealed trisomy 8 mosaicism (47,XY,+8[11]/46,XY[39]). Mosacism was also confirmed by fluorescence in situ hybridization analysis.T8MS is clinically quite heterogeneous and frequently associated with dysmorphism, urogenital abnormalities, corpus callosum agenesis and camptodacty. Deep hand and foot lines are very characteristic for the T8MS. Our patient also had congenital anomalies related to T8MS previously reported in the literature. Correlation of genetic abnormalities with clinical phenotype is always important for the diagnosis of syndromes. In conclusion, chromosomal anomalies should be considered in the differential diagnosis in the dysmorphic patients accompanied by multiple congenital abnormalities and cytogenetic studies sholud be performed first.

Whole-exome sequencing identified a novel heterozygous mutation of SALL1 and a new homozygous mutation of PTPRQ in a Chinese family with Townes-Brocks syndrome and hearing loss

BackgroundPrevious studies have revealed that mutations of Spalt Like Transcription Factor 1 (SALL1) are responsible for Townes-Brocks syndrome (TBS), a rare genetic disorder that is characterized by an imperforate anus, dysplastic ears, thumb malformations and other abnormalities, such as hearing loss, foot malformations, renal impairment with or without renal malformations, genitourinary malformations, and congenital heart disease. In addition, the protein tyrosine phosphatase receptor type Q (PTPRQ) gene has been identified in nonsyndromic hearing loss patients with autosomal recessive or autosomal dominant inherited patterns.MethodsA Chinese family with TBS and hearing loss was enrolled in this study. The proband was a two-month-old girl who suffered from congenital anal atresia with rectal perineal fistula, ventricular septal defect, patent ductus arteriosus, pulmonary hypertension (PH), and finger deformities. The proband’s father also had external ear deformity with deafness, toe deformities and PH, although his anus was normal. Further investigation found that the proband’s mother presented nonsyndromic hearing loss, and the proband’s mother’s parents were consanguine married. Whole-exome sequencing and Sanger sequencing were applied to detect the genetic lesions of TBS and nonsyndromic hearing loss.ResultsVia whole-exome sequencing and Sanger sequencing of the proband and her mother, we identified a novel heterozygous mutation (ENST00000251020: c.1428_1429insT, p. K478QfsX38) of SALL1 in the proband and her father who presented TBS phenotypes, and we also detected a new homozygous mutation [ENST00000266688: c.1057_1057delC, p. L353SfsX8)] of PTPRQ in the proband’s mother and uncle, who suffered from nonsyndromic hearing loss. Both mutations were located in the conserved sites of the respective protein and were predicted to be deleterious by informatics analysis.ConclusionsThis study confirmed the diagnosis of TBS at the molecular level and expanded the spectrum of SALL1 mutations and PTPRQ mutations. Our study may contribute to the clinical management and genetic counselling of TBS and hearing loss.

Unusual features in a child with Marshall-Smith syndrome due to a novel NFIX variant: Evidence for an abnormal protein function

Marshall-Smith syndrome (MSS) is a rare genetic condition characterized by different clinical features, such as accelerated skeletal maturation, growth retardation, neuropsychomotor delay, and characteristic facial abnormalities. This study describes a 2-year-old boy presenting longiline appearance, macrocephalus with trigonocephaly, prominent eyes with bluish sclera, middle face hypoplasia, micrognathia, dysplastic ears, hirsutism, narrow and asymmetrical thorax, hypoplastic scrotal sac, cryptorchidism, joint laxity, hypoplastic toenails, and large sacral dimple with prominent coccyx. Abdominal ultrasonography showed an enlarged left ectopic kidney and skull computed tomography revealed signs of early closure of the metopic suture. High-resolution GTG banding karyotype and high-density CytoScan HD array did not identify abnormalities associated to the patient clinical findings. NFIX sequencing revealed a de novo variant consisted of a seven nucleotides duplication in exon 8. We suggest that some clinical findings, as glaucoma, trigonocephaly and ectopic kidney are underestimated and should be considered within the clinical spectrum of the syndrome. In addition, the NFIX variant identified in our patient is unusual among patients with MSS and has not yet been described in the literature. We present some mechanisms that could be involved in the impairment of proper NFIX protein function.

Fraser syndrome without cryptophthalmos: Two cases

Fraser syndrome (MIM#219000) is an autosomal recessive disorder, characterized by the association of cryptophthtalmos, syndactyly of the four extremities, urinary tract abnormalities and laryngo-tracheal anomalies. This condition is due to homozygous or compound heterozygous mutations in the FRAS/FREM complex genes: FRAS1, FREM2 and GRIP1. Here we report two atypical cases of Fraser syndrome due to mutations in the FRAS1 gene without cryptophthalmos.The first proband had syndactyly of three extremities, bilateral nostril coloboma, dysplastic ears with bilateral conductive hearing loss, blepharophimosis and lacrimal duct abnormalities. FRAS1 sequencing identified two pathogenic compound heterozygous variants: a nonsense variant in exon 70 and a missense variant in exon 24. The second proband had membranous syndactyly of the four extremities, left renal agenesis, laryngeal and ano-rectal malformations, dysplastic ears and bilateral conductive hearing loss. FRAS1 sequencing identified a pathogenic homozygous variant in the last exon of the gene.This first description of molecularly confirmed cases with Fraser syndrome without cryptophthalmos could contribute to further delineation of the clinical spectrum of Fraser syndrome, especially for possible phenotypically milder cases. Larger cohorts are required to try to refer the hypothesis of genotype-phenotype correlation.

EFTUD2 gene deficiency disrupts osteoblast maturation and inhibits chondrocyte differentiation via activation of the p53 signaling pathway

BackgroundMandibulofacial dysostosis with microcephaly (MFDM) is characteristic of multiple skeletal anomalies comprising craniofacial anomalies/dysplasia, microcephaly, dysplastic ears, choanal atresia, and short stature. Heterozygous loss of function variants of EFTUD2 was previously reported in MFDM; however, the mechanism underlying EFTUD2-associated skeletal dysplasia remains unclear.ResultsWe identified a novel frameshift variant of EFTUD2 (c.1030_1031delTG, p.Trp344fs*2) in an MFDM Chinese patient with craniofacial dysmorphism including ear canal structures and microcephaly, mild intellectual disability, and developmental delay. We generated a zebrafish model of eftud2 deficiency, and a consistent phenotype consisting of mandibular bone dysplasia and otolith loss was observed. We also showed that EFTUD2 deficiency significantly inhibited proliferation, differentiation, and maturation in human calvarial osteoblast (HCO) and human articular chondrocyte (HC-a) cells. RNA-Seq analysis uncovered activated TP53 signaling with increased phosphorylation of the TP53 protein and upregulation of five TP53 downstream target genes (FAS, STEAP3, CASP3, P21, and SESN1) both in HCO and in eftud2−/− zebrafish. Additionally, inhibition of p53 by morpholino significantly reduced the mortality of eftud2−/− larvae.ConclusionsOur results confirm a novel de novo variant of the EFTUD2 gene and suggest that EFTUD2 may participate in the maturation and differentiation of osteoblasts and chondrocytes, possibly via activation of the TP53 signaling pathway. Thus, mutations in this gene may lead to skeletal anomalies in vertebrates.

DIAGNOSIS AND MANAGEMENT OF AN INFANT WITH ATYPICAL COMPLETE DIGEORGE IMMUNOLOGIC PHENOTYPE

Introduction The diagnosis of complete DiGeorge syndrome is seen ≤1.5% of patients with 22q11.2 syndrome. We present a rare case of an infant with CHARGE syndrome with atypical complete DiGeorge immunologic phenotype. Case Description A 3-day old Caucasian male was referred for absent TRECs for SCID. He had known arch hypoplasia prior to delivery. Following delivery, a tracheoesophageal fistula was identified. Additional congenital anomalies included large patent ductus arteriosus, bilateral iris colobomas, dysplastic ears, microphallus, cryptorchidism, and bilateral hydronephrosis. His initial lymphocyte enumeration demonstrated absent T-cells, normal number of B-cells and NK-cells. Lymphocyte proliferation to mitogens was absent. Targeted sequencing demonstrated a new variant in CHD7c.2698-11A>G predicted to affect splicing. SCID genetic panel and chromosomal microarray were normal. Based on workups and congenital anomalies, he was diagnosed with CHARGE syndrome with a complete DiGeorge phenotype. At 5 months of age, he developed Omenn syndrome-like manifestations with diffuse non-blanching erythematous macular rash over his body. Serial lymphocyte subsets demonstrated the development of T-cells expressing HLA-DR indicating the emergence of activated T-cells (CD3 269/cumm; CD3+HLA-DR 258/cumm, 96% of total T-cells). Spectratyping confirmed the presence of oligoclonal-T-cells. Therefore, immunosuppression with cyclosporin and prednisolone was given for treatment of self-reactive oligoclonal-T-cells with resolution of rashes. He is currently awaiting thymus transplantation, and receiving IVIG, and antimicrobial prophylaxis. Discussion Although not yet approved by FDA, thymus transplantation is the preferred treatment for complete DiGeorge syndrome. Additionally, close monitoring of activated self-reactive oligoclonal-T-cells symptoms with proper immunosuppressive treatment is crucial while patient is waiting for thymus transplantation.

Mandibulofacial dysostosis Guion-Almeida type caused by novel EFTUD2 splice site variants in two Asian children

Mandibulofacial dysostosis type Guion-Almeida (MFDGA) is a rare disease entity that results in congenital craniofacial anomalies that are caused by abnormal development of the first and second pharyngeal arches. MFDGA is characterized by malar and mandibular hypoplasia, microcephaly, developmental delay, dysplastic ears, and a distinctive facial appearance. Extracraniofacial malformations include esophageal atresia, congenital heart disease, and radial ray abnormalities. Heterozygous mutations in the elongation factor Tu GTP-binding domain containing 2 (EFTUD2) gene have been shown to result in MFDGA. To date, there have been a total of 108 individuals reported in the literature, of whom 95 patients have a confirmed EFTUD2 mutation. The majority of individuals reported in the literature have been of White ethnic origin. Here, we report two individuals of Asian ancestry with MFDGA, each harboring a novel, pathogenic splice site variant in EFTUD2.

7p15 deletion as the cause of hand-foot-genital syndrome: a case report, literature review and proposal of a minimum region for this phenotype

BackgroundHand-foot-genital syndrome (HFGS) is a rare condition characterized by congenital malformations in the limbs and genitourinary tract. Generally, this syndrome occurs due to point mutations that cause loss of function of the HOXA13 gene, which is located on 7p15; however, there are some patients with HFGS caused by interstitial deletions in this region.Case presentationWe describe a pediatric Mexican patient who came to the Medical Genetics Department at the National Institute of Pediatrics because he presented with genital, hand and feet anomalies, facial dysmorphisms, and learning difficulties. Array CGH reported a 12.7 Mb deletion that includes HOXA13.ConclusionsWe compared our patient with cases of HFGS reported in the literature caused by a microdeletion; we found a minimum shared region in 7p15.2. By analyzing the phenotype in these patients, we suggest that microdeletions in this region should be investigated in all patients with clinical characteristics of HFGS who also present with dysplastic ears, mainly low-set implantation with a prominent antihelix, as well as a low nasal bridge and long philtrum.

Determining the frequency of morphological characteristics in a sample of Brazilian children

ObjectiveTo establish the frequency of 82 morphological features in a sample of Brazilian children (between 3 and 13 years old), to understand the influence of age, gender, and ethnicity. MethodsThis was a cross‐sectional study that evaluated 239 children with typical development (between 3 and 13 years old) regarding the presence of 82 morphological characteristics. A previously described protocol, based on the London Dysmorphology Database, was applied to evaluate the sample. This protocol was culturally adapted to Brazilian Portuguese. ResultsThe frequency of 82 morphological characteristics was established in the sample; of 82 characteristics, 50% were considered morphological anomalies (frequency less than 4%). At least 25% of the sample presented more than one minor morphological anomaly. Age was shown to influence the frequency of the following morphological characteristics: widow's peak, prominent antihelix, prominent upper lip, irregular or crowded teeth, and clinodactyly, but had no influence on the frequency of minor morphological anomalies. Gender influenced dysplastic ears and attached earlobe, but had no influence on the frequency of minor morphological anomalies; ethnicity showed influence on camptodactyly and prominent antihelix. A statistically significant divergence was observed regarding 43 of the 73 morphological characteristics that could be compared with literature data (58.9%). ConclusionsThe study determined the frequency of 82 morphological characteristics in 239 children with typical development. Age was the variable that showed more influence on the frequency of morphological characteristics, and comparison with literature data showed that the frequency depends on variables such as age and ethnicity.

Determining the frequency of morphological characteristics in a sample of Brazilian children

ObjectiveTo establish the frequency of 82 morphological features in a sample of Brazilian children (between 3 and 13 years old), to understand the influence of age, gender, and ethnicity. MethodsThis was a cross-sectional study that evaluated 239 children with typical development (between 3 and 13 years old) regarding the presence of 82 morphological characteristics. A previously described protocol, based on the London Dysmorphology Database, was applied to evaluate the sample. This protocol was culturally adapted to Brazilian Portuguese. ResultsThe frequency of 82 morphological characteristics was established in the sample; of 82 characteristics, 50% were considered morphological anomalies (frequency less than 4%). At least 25% of the sample presented more than one minor morphological anomaly. Age was shown to influence the frequency of the following morphological characteristics: widow's peak, prominent antihelix, prominent upper lip, irregular or crowded teeth, and clinodactyly, but had no influence on the frequency of minor morphological anomalies. Gender influenced dysplastic ears and attached earlobe, but had no influence on the frequency of minor morphological anomalies; ethnicity showed influence on camptodactyly and prominent antihelix. A statistically significant divergence was observed regarding 43 of the 73 morphological characteristics that could be compared with literature data (58.9%). ConclusionsThe study determined the frequency of 82 morphological characteristics in 239 children with typical development. Age was the variable that showed more influence on the frequency of morphological characteristics, and comparison with literature data showed that the frequency depends on variables such as age and ethnicity.

Early-onset of ADCK4 glomerulopathy with renal failure: a case report

BackgroundWe present a rare early presentation of a ADCK4-related glomerulopathy. This case is of interest as potentially treatable if genetic results are timely obtained.Case presentationWe report the case of a 5-year-old boy who was identified with significant proteinuria by a urinary routine screening program for school children. Physical examination revealed dysplastic ears and abnormal folded pinna. Albumin level was 41 g/L (39–53 g/L), and urine proteins/creatinine ratio was 2.6 g/g. Renal ultrasound showed enlarged kidneys and perimedullary hyperechogenicity. Treatment by angiotensin-converting-enzyme inhibitor was not beneficial. Renal biopsy showed signs of focal segmental glomerulosclerosis. After 4 years of follow-up, he developed a clinical nephrotic syndrome and no response to prednisone and other immunosuppressive agents was obtained. Within 6 months, he was in end-stage-renal-failure (ESRF) and hemodialysis was started. He was transplanted at 10 years with his mother’s kidney. Genes known to be responsible in steroid-resistant nephrotic syndromes were tested. Our patient is compound heterozygous for two mutations in the aarF domain-containing-kinase 4 (ADCK4) gene. ADCK4 gene is one of the genes involved in coenzyme Q10 (CoQ10) biosynthesis, is located in chromosome 19q13.2 and expressed in podocytes. ADCK4 mutations show a largely renal-limited phenotype. The nephropathy usually presents during adolescence, fast evolves towards ESRF, and may be treatable by CoQ10 supplementation if started early in the disease. Our patient presented nephrotic range proteinuria at 5 years, and he reached ESRF at 10 years.ConclusionADCK4-related glomerulopathy is an important novel and potentially treatable cause of isolated nephropathy not only in adolescents, but also in children in their first decade of life. Discovery of important proteinuria in an asymptomatic child should prompt early genetic investigations.