Frontonasal Dysplasia, Severe Neuropsychological Delay, and Midline Central Nervous System Anomalies: Report of 10 Brazilian Male Patients

Here we report on 10 male patients with frontonasal dysplasia, cleft lip/palate, mental retardation, lack of language acquisition, and severe central nervous system involvement. Imaging studies disclosed absence of the corpus callosum, midline cysts, and an abnormally modeled cerebellum. Neuronal heterotopias were present in five patients and parieto-occipital encephalocele in three patients. We suggest that this pattern found exclusively in males, most likely represents a newly recognized syndrome distilled from the group of disorders subsumed under frontonasal dysplasia. (C) 2009 Wiley-Liss, Inc.

Holoprosencephaly, Ectrodactyly, and Bilateral Cleft of Lip and Palate: Exclusion of SHH, TGIF, SIX3, GLI2, TP73L, and DHCR7 as Candidate Genes

We describe a Brazilian boy with semilobar holoprosencephaly, ectrodactyly, bilateral cleft of lip and palate, and severe mental retardation. The karyotype was normal and the screening for mutations in the genes SHH, TGIF, SIX3, GLI2 TP73L, and DHCR7 did not show any change. This rare condition was described previously in seven male patients. Clinical and genetic aspects are discussed. (C) 2009 Wiley-Liss, Inc.

UBE2A Deficiency Syndrome: Mild to Severe Intellectual Disability Accompanied by Seizures, Absent Speech, Urogenital, and Skin Anomalies in Male Patients

We describe three patients with a comparable deletion encompassing SLC25A43, SLC25A5, CXorf56, UBE2A, NKRF, and two non-coding RNA genes, U1 and LOC100303728. Moderate to severe intellectual disability (ID), psychomotor retardation, severely impaired/absent speech, seizures, and urogenital anomalies were present in all three patients. Facial dysmorphisms include ocular hypertelorism, synophrys, and a depressed nasal bridge. These clinical features overlap with those described in two patients from a family with a similar deletion at Xq24 that also includes UBE2A, and in several patients of Brazilian and Polish families with point mutations in UBE2A. Notably, all five patients with an Xq24 deletion have ventricular septal defects that are not present inpatients with a point mutation, which might be attributed to the deletion of SLC25A5. Taken together, the UBE2A deficiency syndrome in male patients with a mutation in or a deletion of UBE2A is characterized by ID, absent speech, seizures, urogenital anomalies, frequently including a small penis, and skin abnormalities, which include generalized hirsutism, low posterior hairline, myxedematous appearance, widely spaced nipples, and hair whorls. Facial dysmorphisms include a wide face, a depressed nasal bridge, a large mouth with downturned corners, thin vermilion, and a short, broad neck. (C) 2010 Wiley-Liss, Inc.

Achados audiológicos e eletrofisiológicos de indivíduos com a síndrome G/BBB

A síndrome G/BBB é uma condição rara, caracterizada por hipertelorismo, fissura de lábio e palato e hipospádia. Não foram encontrados trabalhos sobre a audição em indivíduos com esta síndrome. OBJETIVO: Investigar a função auditiva em pacientes com síndrome G/BBB quanto à ocorrência ou não de perda auditiva e a condução nervosa auditiva periférica e central. MATERIAL E MÉTODO: Catorze pacientes de 7 a 34 anos, do gênero masculino, com a síndrome G/BBB, foram avaliados por meio de otoscopia, audiometria, timpanometria e potenciais evocados auditivos de tronco encefálico (PEATE). Forma de Estudo: Estudo de série clínico prospectivo. RESULTADOS: Limiares audiométricos normais em 12 (66,7%) pacientes da amostra e alterados em dois (33,3%), sendo um com perda condutiva e um neurossensorial. Quanto ao PEATE, foram encontrados: latências absolutas da onda I normais em todos os pacientes, aumento das latências absolutas da onda III e V em dois e seis pacientes respectivamente; latências interpicos I-III, III-V e I-V aumentadas em quatro, três e oito pacientes, respectivamente. CONCLUSÃO: Perdas auditivas periféricas podem ocorrer na síndrome G/BBB. Há evidências de comprometimento das vias auditivas centrais em nível do tronco encefálico. Estudos com exames de imagem são necessários para maior clareza dos achados clínicos.

A case of Zimmermann-Laband syndrome with supernumerary teeth

Background: Zimmermann-Laband syndrome is a rare autosomal dominant disorder that is characterized by gingival fibromatosis, ear, nose, bone, and nail defects, and hepatosplenomegaly.Methods: This case report describes the clinical presentation and periodontal findings in a 13-year-old female patient with previously undiagnosed Zimmermann-Laband syndrome.Results: Clinical and radiographic findings and genetic counseling confirmed the diagnosis of Zimmermann-Laband syndrome. The most striking oral findings were the presence of gingival enlargement involving both the maxillary and mandibular arches, anterior open bite, non-erupted teeth, and two supernumerary teeth. Periodontal treatment consisted of gingivectomy in four quadrants. Histopathologic evaluation of excised tissue supported the diagnosis of gingival fibromatosis. The patient was referred for appropriate orthodontic treatment and genetic counseling, and has been closely followed for the earliest signs of hepatosplenomegaly.Conclusions: Dental practitioners should be alert for developmental abnormalities that may occur in patients with gingival fibromatosis as this may indicate the presence of a rare disorder like Zimmermann-Laband syndrome. A comprehensive medical history and physical systemic evaluation are essential for correct diagnosis and treatment of these cases.

MICHELS SYNDROME IN A BRAZILIAN GIRL BORN TO CONSANGUINEOUS PARENTS

We report on a Brazilian girl born to consanguineous parents and presenting with craniosynostosis, telecanthus, blepharophimosis, blepharoptosis, epicanthus inversus, cleft lip and palate, skeletal defects, and hearing loss. This combination of anomalies appears to constitute the Michels syndrome. (C) 1995 Wiley-Liss, Inc.

Clinical manifestations and oral findings in fraser syndrome

This article is the first known case report of Fraser syndrome in the dental literature. Its purpose was to present the clinical manifestations, oral findings, and dental treatment of a 14-year, 10-month-old female patient. Fraser syndrome is a rare recessive autosomal genetic disorder characterized by multisystemic malformation, usually comprising cryptophthalmos, syndactyly, and renal defects. The child presented with: (1) hydrocephaly; (2) face asymmetry; (3) low-inserted ears; (4) flat nose bridge; (5) cryptophthalmos; (6) bilateral absence of eyeballs; (7) hypertelorism; (8) syndactyly on the left fingers and toes; (9) skeletal defects; and (10) lower limb asymmetry. The intraoral examination revealed: (1) complete primary denture; (2) malocclusion; (3) tooth crowding; (4) ogival palate; (5) normal labial frena; (6) absence of lingual frenum (not compromising the tongue movements); (7) parched lips; (8) supragingival calculus adhered to all tooth surfaces; and (9) moderate gingivitis. The dental treatment consisted of periodic monitoring of the patient's oral health status and supragingival scaling associated with topical applications of 0.12% chlorhexidine digluconate gel at 2-week intervals to reduce gingivitis.

Frontonasal dysplasia: clinical evaluation on audiological and brainstem electrophysiological profiles

Frontonasal dysplasia (FND) is a rare malformative complex affecting the frontal portion of the face, the eyes and the nose; it may occur singly or associated with other clinical signs. No systematic studies describing hearing in this condition were found. AIM: To evaluate hearing sensitivity and sound stimulus conduction from cochlea to brainstem in patients with clinical signs of FND. METHODS: 21 patients with isolated or syndromic FND were submitted to a clinical (otological/vestibular antecedents and otoscopy) and instrumental (pure tone and speech audiometry, tympanometry and brainstem auditory evoked response) hearing evaluation. DESIGN: A clinical, cross-sectional observational prospective study. RESULTS: Hearing thresholds were normal in 15 (70%) patients, abnormal in 5 (25%), mostly with conductive hearing loss; one patient did not cooperate with testing. The tympanometric curve was type A in 30 (72%) ears, type C in 5 (12%), type As in 4 (9%) and type B in 3 (7%). The auditory brainstem response (ABR) showed no abnormalities. CONCLUSION: Patients with FND showed no abnormalities in the auditory system from cochlea to brainstem in this study. Mild conductive hearing loss found in some is probably related to cleft palate. Further evaluation of hearing pathways at higher levels is recommended.

A familial case with interstitial 2q36 deletion: Variable phenotypic expression in full and mosaic state

Submicroscopic chromosomal anomalies play an important role in the etiology of craniofacial malformations, including midline facial defects with hypertelorism (MFDH). MFDH is a common feature combination in several conditions, of which Frontonasal Dysplasia is the most frequently encountered manifestation; in most cases the etiology remains unknown. We identified a parent to child transmission of a 6.2 Mb interstitial deletion of chromosome region 2q36.1q36.3 by array-CGH and confirmed by FISH and microsatellite analysis. The patient and her mother both presented an MFDH phenotype although the phenotype in the mother was much milder than her daughter. Inspection of haplotype segregation within the family of 2q36.1 region suggests that the deletion arose on a chromosome derived from the maternal grandfather. Evidences based on FISH, microsatellite and array-CGH analysis point to a high frequency mosaicism for presence of a deleted region 2q36 occurring in blood of the mother. The frequency of mosaicism in other tissues could not be determined. We here suggest that the milder phenotype observed in the proband's mother can be explained by the mosaic state of the deletion. This most likely arose by an early embryonic deletion in the maternal embryo resulting in both gonadal and somatic mosaicism of two cell lines, with and without the deleted chromosome. The occurrence of gonadal mosaicism increases the recurrence risk significantly and is often either underestimated or not even taken into account in genetic counseling where new mutation is suspected. (C) 2012 Elsevier Masson SAS. All rights reserved.

Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes

Craniofrontonasal syndrome (CFNS), an X-linked disorder caused by loss-of-function mutations of EFNB1, exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis and additional minor malformations, but males are usually more mildly affected with hypertelorism as the only feature. X-inactivation is proposed to explain the more severe outcome in heterozygous females, as this leads to functional mosaicism for cells with differing expression of EPHRIN-B1, generating abnormal tissue boundaries-a process that cannot occur in hemizygous males. Apparently challenging this model, males occasionally present with a more severe female-like CFNS phenotype. We hypothesized that such individuals might be mosaic for EFNB1 mutations and investigated this possibility in multiple tissue samples from six sporadically presenting males. Using denaturing high performance liquid chromatography, massively parallel sequencing and multiplex-ligation-dependent probe amplification (MLPA) to increase sensitivity above standard dideoxy sequencing, we identified mosaic mutations of EFNB1 in all cases, comprising three missense changes, two gene deletions and a novel point mutation within the 5' untranslated region (UTR). Quantification by Pyrosequencing and MLPA demonstrated levels of mutant cells between 15 and 69%. The 5' UTR variant mutates the stop codon of a small upstream open reading frame that, using a dual-luciferase reporter construct, was demonstrated to exacerbate interference with translation of the wild-type protein. These results demonstrate a more severe outcome in mosaic than in constitutionally deficient males in an X-linked dominant disorder and provide further support for the cellular interference mechanism, normally related to X-inactivation in females.