Broad Nasal Root Research Articles

Waardenburg syndrome

Waardenburg syndrome is a rare inherited and genetically heterogenous disorder of neural crest cell development. Four distinct subtypes showing marked interfamilial and intrafamilial variability have been described. We report a girl showing constellation of congenital hearing impairment with 110 dB and 105 dB loss in right and left ear respectively, hypoplastic blue iridis, white forelock, dystopia canthorum and broad nasal root. Other affected relatives of the family, with variable features of the syndrome, have been depicted in the pedigree.

Molecular cytogenetic characterization of a familial der(1)del(1)(p36.33)dup(1)(p36.33p36.22) with variable phenotype

Chromosome deletions involving 1p36 are the most common known terminal rearrangements occurring at a frequency of approximately 1 in 5,000 live births. In contrast, duplications of the same region have been reported rarely. We describe a familial rearrangement der(1)del(1)(p36.33)dup(1)(p36.33p36.22) identified in a mother, daughter, and son. These individuals help define a syndrome with variable mental disability, attention deficit-hyperactivity disorder, and a distinctive facial appearance with wide palpebral fissures, broad nasal root, macrostomia, ear malformations, and prominent incisors. Based on our results we suggest that the complex rearrangement seen in our family could be the result of the breakage-fusion-bridge (BFB) cycles model of formation.

Cochlear implantation in children with Waardenburg syndrome

Waardenburg syndrome is an autosomal-dominant trait resulting from mutations occurring in different genes. It is often characterized by varying degrees of: congenital hearing loss; dystopia canthorum; synophrys; broad nasal root; depigmentation of hair (white forelock), skin or both; and heterochromic or hypochromic irides. A retrospective case study was done to assess speech perception, speech production, general intelligence and educational setting in six profoundly hearing-impaired children with Waardenburg syndrome (four with type I, one with type II and one with type III) ranging in age from two years to 14 years, seven months (mean = six years, six months). None of the patients had malformation of the cochlea and were implanted using Nucleus 22/24 and Med-el combi40+. Five out of the six cases were of average intelligence and one had a borderline intelligence quotient. The follow-up period ranged from one year, 10 months to six years, six months (mean = three years, six months) after implantation. The evaluation of auditory perception in patients was accomplished using the Persian Auditory Perception Test for the Hearing-Impaired, a Persian Spondee words test and the Categories of Auditory Performance Index. The Speech Intelligibility Rating test was used to evaluate speech production ability. All the patients' speech perception and speech intelligibility capabilities improved considerably after receiving the implants, and they were able to be placed in regular educational settings. Patients used their cochlear-implant devices whenever awake, implying that they benefitted from the devices. We suggest that any further expansion of cochlear-implantation criteria in children include those with Waardenburg syndrome.

Chromosome 22q11.2 deletion syndrome: an underestimated cause of neuropsychiatric impairment in adolescence

Sirs: Chromosome 22q11.2 deletion syndrome is a common multiple malformation syndrome estimated to affect between 1 in 4000 and 1 in 5000 individuals [1]. With the advent of molecular genetics a 3-Mb microdeletion within 22q11 was found to underlie a heterogeneous group of disorders with overlapping features, such as Di George and velocardiofacial syndrome [2, 3]. The phenotype of the disorder has expanded considerably within the last few years, whereas the clinical features vary significantly among affected individuals [4]. However, cardiovascular defects, immunological deficits, neurodevelopmental retardation, craniofacial abnormalities and hypocalcemia are recognised as the major and most frequent manifestations of the syndrome [5]. A 17-year-old boy presented with a gradual cognitive and behavioral decline over the last 18 months. The symptom onset coincided with a febrile gastrointestinal tract infection and was initially characterized by anxiety, altered sleep pattern, bizarre statements and actions and lack of initiative. The patient exhibited bland, and at times inappropriate affect, whereas his thought and behavior were mildly but progressively disorganised. The patient became eventually socially withdrawn and was unable to attend to his school activities. However, no hallucinations or delusions were present. He showed poor response to neuroleptic medication and remained withdrawn with psychomotor retardation and poverty of speech. His past medical history was significant for non-febrile neonatal seizures, which were attributed to hypocalcemia. At that time, he was diagnosed as having hypoparathyroidism, whereas further investigation showed thymic hypoplasia with marginally reduced T-cell numbers. However, no chromosomal abnormality was found on karyotyping. Developmental milestones were also delayed; he began to walk at 17 months and first combined single words into full sentences around 48 months of age. The patient had attended regular school classes, but his overall school performance had always been poor with prominent deficits in visuo-spatial abilities and executive functioning. He was also diagnosed as having bilateral stenosis of the external auditory canal, and an inguinal hernia had been repaired at 3 months of age. Moreover, the patient had an episode of septicemia due to pneumococcal infection at the age of 13. His family history was unremarkable, apart from a diagnosis of schizophrenia in a paternal great uncle. The patient was admitted and evaluated mainly by the neurology services. On examination, he was noted to have slightly dysmorphic facial features consisting of broad nasal root, malar flattening and relative retrognathia. His speech was hypernasal without overt cleft palate, but the general neurological and physical examination were otherwise unremarkable. Neuropsychological assessment revealed moderate deficits on verbal, as well as non-verbal reasoning tests, whereas the patient’s visual perceptual skills and memory appeared to be mildly impaired. The prominent difficulty of the patient in sustaining concentration exaggerated his deficits, but his overall neuropsychological profile was consistent with significant cerebral dysfunction. Routine hematology showed mild thrombocytopenia, increased free thyroxin values and marginally decreased calcium levels. Routine EEGs revealed on one occasion brief bursts of generalised epileptiform activity; however, successive EEGs as well as video-EEG monitoring failed to detect any abnormality. MRI of the brain using volumetric acquisition as well as echocardiogram proved normal. The patient was then extensively investigated in a tertiary university centre in order to exclude an underlying neurological disorder. Blood films for acanthocytes, serum copper and ceruloplasmin, slit lamp examination, antibasalganglia antibodies, white cell enzymes as well as very long chain fatty acids, plasma amino acids and urine organic acids were either normal or negative. The suspicious EEG findings led to skin biopsy for Lafora disease, which revealed no abnormality. Subsequently, a muscle biopsy was undertaken which provided no evidence for a mitochondrial encephalomyopathy. Finally, on readmission 2 years later a fluorescence in-situ hybridization (FISH) using the N25 probe was performed, which demonstrated a microdeletion within chromosome 22q11.2. It is well established that individuals with chromosome 22q11.2 deletion syndrome are at risk to develop a range of psychiatric illnesses. Early reports cite a high prevalence of psychotic disorders, specifically schizophrenia, among adults carrying the deletion and LETTER TO THE EDITORS

A variant Cri du Chat phenotype and autism spectrum disorder in a subject withde novocryptic microdeletions involving 5p15.2 and 3p24.3‐25 detected using whole genomic array CGH

Cri du Chat syndrome (CdCs) is a well-defined clinical entity, with an incidence of 1/15,000 to 1/50,000. The critical region for CdCs has been mapped to 5p15, with the hallmark cat-like cry sublocalized to 5p15.3 and the remaining clinical features to 5p15.2. We report findings in a subject with a de novo t(5;7)(p15.2;p12.2) and an inv(3)(p24q24), who was found to have a cryptic microdeletion in the critical region for CdCs detected using a 1-Mb genomic microarray. In addition to 5p deletion, the proband had a de novo single clone loss at the 3p breakpoint of inv(3)(p24q24) and a familial single clone deletion at 18q12. Deletions were confirmed using microsatellite analysis and fluorescence in situ hybridization. The 5p deletion encompasses approximately 3 Mb, mapping to the border between bands 5p15.2 and 5p15.31. The single clone deletion on chromosome 3 maps to 3p24.3-3p25, for which there is no known phenotype. The clinical features of our proband differ from the characteristic CdC phenotype, which may reflect the combined effect of the two de novo microdeletions and/or may further refine the critical region for CdCs. Typical features of CdCs that are present in the proband include moderate intellectual disability, speech, and motor delay as well as dysmorphic features (e.g. broad and high nasal root, hypertelorism, and coarse facies). Expected CdCs features that are not present are growth delay, microcephaly, round facies, micrognathia, epicanthal folds, and the signature high-pitched cry. Behavioral traits in this subject included autism spectrum disorder, attention-deficit hyperactivity disorder, and unmanageable behavior including aggression, tantrums, irritability, and self-destructive behavior. Several of these behaviors have been previously reported in patients with 5p deletion syndrome. Although most agree on the cat-cry critical region (5p15.3), there is discrepancy in the precise location and size of the region associated with the more severe manifestations of CdCs. The clinical description of this proband and the characterization of his 5p deletion may help to further refine the phenotype-genotype associations in CdCs and autism spectrum disorder.

A new autosomal recessive oto-facial syndrome with midline malformations

Two sisters from a Lebanese family presented with slight developmental delay, short stature, congenital microcephaly, frontal bossing, mild hyperplastic supra-orbital ridges, broad nasal root, small dysplastic low-set ears, high arched palate, short neck, and hearing impairment. In addition, the oldest affected sister had esophageal atresia and the other sister had cleft palate. Temporal bone abnormalities included hypoplasia of the external auditory canal, small middle ear cavity, abnormal ossicles, and inner ear malformations with enlarged vestibular acqueducts. Differential diagnosis is discussed, and the possibility of a newly recognized autosomal recessive syndrome is raised.

Rapp-Hodgkin syndrome

A 5-year-old boy with a history of a bifid uvula and a submucosal cleft palate presented for evaluation of brittle nails. The physical examination demonstrated cup-shaped ears, a broad nasal root, thin upper lip, mid-facial hypoplasia, coarse hair, and twenty-nail dystrophy. The clinical presentation of ectodermal dysplasia with cleft palate was consistent with Rapp-Hodgkin syndrome, which is one of several allelic diseases associated with mutations in the TP63 gene. The clinical manifestations of Rapp-Hodgkin as well as other ectodermal dysplasias with clefting are discussed.

Chromosome 22q11.2 microdeletion in a patient with hemophilia A

We report a 6-year-old patient with hemophilia A, who also exhibited clinical features typical of 22q11.2 deletion syndrome (22qDS). The specific traits were mild mental retardation, speech delay, hypernasal speech, deficits in voice quality and articulation, narrow palpebral fissures, broad and depressed nasal root, high-arched palate, microstomia, and overfolded ears. The patient had no associated congenital cardiac or palatal malformations. It can be particularly difficult to identify this syndrome in newborns and infants without congenital heart defects. This case underlines that microdeletion of chromosome 22q11.2 should be considered in any patient who exhibits typical clinical features of 22qDS, regardless of whether they have another single-gene disorder.

Otolaryngological manifestations of cleidocranial dysplasia, concentrating on audiological findings.

Cleidocranial dysplasia is an autosomal dominant skeletal syndrome characterized by open skull sutures and clavicular hypoplasia or aplasia. It results from mutations in the transcription factor CBFA1 required for osteoblast differentiation and normal bone formation. Therefore, mutations in CBFA1 would be expected to cause conductive or sensorineural hearing loss, or both. The objective of the study was to evaluate the auditory function and head and neck manifestations of patients with cleidocranial dysplasia. Case series. Patients with cleidocranial dysplasia who were identified from the case records of the Craniofacial Anomalies Center at the University of California San Francisco (San Francisco, CA) gave medical and developmental history, underwent a general physical examination and a thorough head and neck examination, and completed a comprehensive audiological evaluation. Four families with eight affected individuals in all and one sporadic case were studied. The nine patients showed highly variable expression of abnormalities. Head and neck examination demonstrated abnormal cranial sutures, broad nasal root, clavicular hypoplasia or aplasia, and abnormally high arched palate. Although seven of nine patients showed eustachian tube dysfunction, recurrent otitis media in childhood requiring surgical intervention was not common. Hearing loss was present in three of nine patients (33%). One patient had a 40-dB mixed hearing loss, the second had a 25-dB low-frequency conductive hearing loss, and the third had a 45-dB high-frequency sensorineural hearing loss. In patients with cleidocranial dysplasia, eustachian tube dysfunction, conductive hearing loss, and sensorineural hearing loss are common because of structural and functional changes of the temporal bone and palate. Therefore, patients with cleidocranial dysplasia should be evaluated routinely by an otolaryngologist and undergo complete audiological testing.

Optic disc coloboma (the morning glory syndrome) and optic nerve coloboma associated with transsphenoidal meningoencephalocele

The association optic disc coloboma (the morning glory syndrome), optic nerve coloboma, and transsphenoidal meningoencephalocele is extremely rare. We describe an original case of optic disc coloboma in association with optic nerve coloboma, microphthalmos, optic nerve hypoplasia, and transsphenoidal meningoencephalocele. There were no midfacial anomalies (hypertelorism, broad nasal root, cleft lip, and cleft plate) and pituitary dysfunction. For patients who had optic disc-nerve coloboma without midfacial anomalies, neuroimaging should be prompted to look for transsphenoidal encephalocele/meningoencephalocele and other anomalies. We present demonstrative fundoscopic pictures, ultrasound and magnetic resonance imaging of this original case of a 7-year-old patient.

Further evidence from two families that craniofrontonasal dysplasia maps to Xp22.

Craniofrontonasal dysplasia (CFND) is a rare X-linked disorder that maps to a 13-cM region on Xp22. Phenotypic features include craniosynostosis, hypertelorism and a broad nasal root with or without a bifid nasal tip. Multiple examples have been reported of males having a less severe phenotype than females. We report haplotype analyses in two CFND families over the critical region to which the gene has been mapped. In pedigree 1, a clinically unaffected male inherited the affected marker haplotype spanning the critical region. We suggest that this individual does have the CFND mutation, but has an extremely mild phenotype that is not detectable with clinical examination. Under the assumption that he is an unknown phenotype, a combined two-point LOD score of 1.68 at zero recombination was obtained, increasing the previously reported total to 5.61 (DXS8022). The data do not narrow down the critical region. This result stresses the importance of subjecting fathers of apparently sporadic cases to a highly critical medical examination and may also explain the unequal ratio of reported female-to-male cases.

Frontonasal dysplasia, macroblepharon, eyelid colobomas, ear anomalies, macrostomia, mental retardation, and CNS structural anomalies. A new syndrome?

We report a Brazilian girl, born to normal and non-consanguineous parents and presenting, among other signs, brachyacrocephaly, a wide forehead, hypertelorism, wide palpebral fissures with multiple eyelid colobomas, a broad and high nasal root, an absent nasal tip, a wide columella, a long and smooth philtrum, a carp-like mouth, macrostomia, a thin upper lip with midline notching, submucous cleft of the soft palate, a small and grooved chin, ear anomalies, Dandy-Walker anomaly, a structural anomaly of the corpus callosum, grey matter heterotopia, and mental retardation. The whole clinical picture of the present patient suggests a 'new' type of frontonasal dysplasia and main differential diagnosis includes the acrofrontofacionasal dysostosis 2 syndrome (MIM 201181). Other differential diagnoses are discussed.

Craniotubular dysplasia with severe postnatal growth retardation, mental retardation, ectodermal dysplasia, and loose skin: Lenz-Majewski-Like syndrome

The heterogeneous group of craniotubular dysplasias is characterized by modeling errors of the craniofacial and tubular bones. Some conditions in this category cause not only skeletal abnormalities but also a variety of mesoectodermal dysplasias, as exemplified in Lenz-Majewski syndrome (MIM 151050), which comprises craniodiaphyseal dysplasia, failure to thrive, mental retardation, proximal symphalangism, enamel hypoplasia, and loose skin. We report on a boy with a hitherto unknown multisystem disorder, including skeletal changes that were regarded as a form of craniotubular dysplasia. The patient had a large head, exophthalmos, a broad nasal root, anteverted nostrils, large auricles, thick lips, micrognathia, severe postnatal growth retardation with emaciation, severe mental retardation, sparse hair growth, enamel hypoplasia, and thin, loose skin with hyperlaxity. Skeletal changes consisted of thickened calvaria, sclerosis of the skull base and facial bones, thick ribs, and metaphyseal undermodeling of the tubular bones. In addition, generalized osteopenia was evident. The present disorder overlaps phenotypically with Lenz-Majewski syndrome; nevertheless, the absence of diaphyseal hyperostosis and proximal symphalangism in the present patient was not consistent with Lenz-Majewski syndrome.

Craniotubular dysplasia with severe postnatal growth retardation, mental retardation, ectodermal dysplasia, and loose skin: Lenz‐Majewski‐Like syndrome

The heterogeneous group of craniotubular dysplasias is characterized by modeling errors of the craniofacial and tubular bones. Some conditions in this category cause not only skeletal abnormalities but also a variety of mesoectodermal dysplasias, as exemplified in Lenz-Majewski syndrome (MIM 151050), which comprises craniodiaphyseal dysplasia, failure to thrive, mental retardation, proximal symphalangism, enamel hypoplasia, and loose skin. We report on a boy with a hitherto unknown multisystem disorder, including skeletal changes that were regarded as a form of craniotubular dysplasia. The patient had a large head, exophthalmos, a broad nasal root, anteverted nostrils, large auricles, thick lips, micrognathia, severe postnatal growth retardation with emaciation, severe mental retardation, sparse hair growth, enamel hypoplasia, and thin, loose skin with hyperlaxity. Skeletal changes consisted of thickened calvaria, sclerosis of the skull base and facial bones, thick ribs, and metaphyseal undermodeling of the tubular bones. In addition, generalized osteopenia was evident. The present disorder overlaps phenotypically with Lenz-Majewski syndrome; nevertheless, the absence of diaphyseal hyperostosis and proximal symphalangism in the present patient was not consistent with Lenz-Majewski syndrome. Am. J. Med. Genet. 71:87–92, 1997. © 1997 Wiley-Liss, Inc.

Segregation of a familial balanced (12;10) insertion resulting in dup(10)(q21.2q22.1) and del(10)(q21.2q22.1) in first cousins

An interchromosomal insertion in 3 generations of a family was ascertained through two developmentally delayed first cousins. Cytogenetic analysis using G-banding and chromosome painting showed an apparently balanced direct insertion of chromosome 10 material into chromosome 12, ins(12;10)(q15;q21.2q22.1), in the mothers and grandfather of these children. The proposita inherited only the derivative 10 chromosome, resulting in deletion of 10q21.2 → 22.1 while her cousin inherited only the derivative 12, resulting in duplication of 10q21.2 → 22.1. A comparison of the proposita with published deletion cases suggests a pattern of anomalies attributable to deletion of the 10q21 → q22 region: developmental delay, hypotonia, a heart murmur, telecanthus, broad nasal root and ear abnormalities. This is the first report of a nontandem duplication of the 10q21 → q22 region. The phenotype of the cousin with the duplication does not overlap greatly with published tandem 10q duplications. Finally, this report reaffirms the importance of obtaining family studies of patients with interstitial chromosomal abnormalities. Am J. Med. Genet. 69:188–193, 1997. © 1997 Wiley-Liss, Inc.

Segregation of a familial balanced (12;10) insertion resulting in dup(10)(q21.2q22.1) and del(10)(q21.2q22.1) in first cousins

An interchromosomal insertion in 3 generations of a family was ascertained through two developmentally delayed first cousins. Cytogenetic analysis using G-banding and chromosome painting showed an apparently balanced direct insertion of chromosome 10 material into chromosome 12, ins(12;10)(q15;q21.2q22.1), in the mothers and grandfather of these children. The proposita inherited only the derivative 10 chromosome, resulting in deletion of 10q21.2 --> 22.1 while her cousin inherited only the derivative 12, resulting in duplication of 10q21.2 --> 22.1. A comparison of the proposita with published deletion cases suggests a pattern of anomalies attributable to deletion of the 10q21 --> q22 region: developmental delay, hypotonia, a heart murmur, telecanthus, broad nasal root and ear abnormalities. This is the first report of a nontandem duplication of the 10q21 --> q22 region. The phenotype of the cousin with the duplication does not overlap greatly with published tandem 10q duplications. Finally, this report reaffirms the importance of obtaining family studies of patients with interstitial chromosomal abnormalities.

Multiple antimicrobial resistance of pneumococci in children with otitis media, bacteremia, and meningitis in slovakia: Reichler M.R.; Rakovsky J.; Sobotova A.; Slacikova M.; Hlavacova B.; Hill B.; Krajcikova L.; Tarina P.; Facklam R.R.; Breiman R.F.J. Infect. Dis. (1995) 171/6 (1491–1496)

The Waardenburg's syndrome, a congenital ectodermal germ layer defect of autosomal dominant inheritance with variable phenotypic expressivity consists of 6 major characteristics: dystopia canthorum, broad nasal root, hypoplasia of the medial eyebrow, heterochromia irides, white forelock, and congenital deafness. Twelve additional characteristics have been reported including meningocele, atresia of the esophagus, and Hirshsprung's disease supporting an early hypothesis that the neural crest is the embryonic site linking defects of the cervical sympathic system with pigmentary abnormalities and inner ear anomalies.Congenital deafness reported in 20% of Waardenburg patients, and the most disabling characteristic, has been associated with ENG abnormalities in 30% of these deaf patients. A congenitally deaf young person with Waardenburg's syndrome is examined for basic cause of episodic vertiginous symptoms. Diagnostic assistance from previous investigations is lacking because they have not involved state-of-the-art functional evaluations or correlations of behavioral and radiographic findings. In this patient, high-resolution computerized tomography failed to demonstrate bony labyrinthine anomalies. Functional cochleovestibular analysis revealed a bilateral profound sensorineural hearing loss and a unilateral weakness in oculomotor responses to caloric stimulations. Repeated measurements of ocular counterroll show variations compatible with intermittent otolithic dysfunctioning. These findings are consistent with a diagnosis of an acquired active unilateral peripheral vestibular disorder. Some of the technical issues underlying the derivation of this conclusion are discussed.

Spontaneous Contraction of Leukodermic Patches in Waardenburg Syndrome

Waardenburg Syndrome is an autosomal dominantly inherited disorder with variable penetrance. It is a rare disorder with an estimated frequency of 1:20,000 in Kenya (East Africa) and 1:40,000, in the Netherlands presenting with or without deafness. The frequency with deafness is lower, estimated at 1:50,000 to 1:212,000. The major characteristic features are as follows, with reported incidences in parenthesis: 1) Dystopia canthorum (99%); 2) synophrys (17%-69%); 3) broad nasal root (78%); 4) depigmentation of hair, skin, or both (17%-58% with white forelock); 5) heterochromic or hypochromic irides (greater than 20%); 6) congenital deafness (9%-38%). Genetic heterogeneity has led to classification of affected families as type I, with dystopia canthorum, or type II, without dystopia canthorum (2, 6). Piebaldism and Woolf's Syndrome can present with pigmentary changes which are similar to Waardenburg Syndrome. Woolf's Syndrome also includes deafness. However, the distinguishing structural ophthomologic abnormalities of dystopia canthorum, broad nasal root, and synophrys are not found in either piebaldism or Woolf's Syndrome. The congenital patterns of leukoderma in both piebaldism and Waardenburg Syndrome has been believed to be stable throughout the lifetime of the affected individuals. We report an otherwise typical family with Waardenburg Syndrome, type I, in which 2 members atypically demonstrate spontaneous pigmentation and contraction of congenital leukodermic patches. To our knowledge, this has not been previously reported in Waardenburg Syndrome.

基底細胞母斑症候群例

The basal cell nevus syndrome (Gorlin-Goltz syndrome) is an autosomal dominant disorder. It is characterized by multiple basal cell nevi, multiple odontogenic keratocysts and skeletal abnormalities (ex. bifurcated rib, scoliosis).Few reports of its clinical features have been published in the oto-rhino-laryngological literature. The diagnostic criteria are not yet clear, except in patients with co-existing skin anomalies and keratocysts. A 20-year-old male visited our clinic with a chief complaint of pain and swelling around the right bucca. He had multiple jaw cysts with an impacted tooth, cysts in both maxillary sinuses with an impacted tooth, protrusion of the frontal bone, a broad nasal root, increased distance between the inner canthi of the eyes, and mental retardation.The histologic diagnosis of multiple jaw cysts and maxillary cysts was odontogenic keratocysts. So far, there has been no recurrence since the operation.

Facio‐cardio‐renal (Eastman‐Bixler) syndrome

We report on a 5-year-old boy with moderate mental retardation, horseshoe kidneys, tricuspid valve prolapse, and a characteristic face with broad nasal root, prominent ears, and a cleft palate. These manifestations suggested the diagnosis of the Eastman-Bixler syndrome. Our patient also had an isolated growth hormone deficiency which responded successfully to treatment.