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Bone ; 153: 116152, 2021 12.
Article En | MEDLINE | ID: mdl-34400385

Acrofrontofacionasal dysostosis type 1 (AFFND1) is an extremely rare disorder characterized by several dysmorphic features, skeletal abnormalities and intellectual disability, and described only in seven patients in the literature. A biallelic variant in the Neuroblastoma Amplified Sequence (NBAS) gene was recently identified in two Indian patients with AFFND1. Here we report genetic investigation of AFFND1 in the originally described Brazilian families and the identification of an extremely rare, recessively-inherited, intronic variant in the Phosphatidylinositol Glycan class B (PIGB) gene NC_000015.10 (NM_004855.4): c.795-19T > G) in the affected individuals. The PIGB gene encodes an enzyme involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor, which is required for the post-translational modification of a large variety of proteins, enabling their correct cellular localization and function. Recessive variants in PIGB have previously been reported in individuals with a neurodevelopmental syndrome having partial overlap with AFFND1. In vitro assays demonstrated that the intronic variant leads to exon skipping, suggesting the Brazilian AFFND1 patients may be null for PIGB, in agreement with their severe clinical phenotype. These data increase the number of pathogenic variants in the PIGB gene, place AFFND1 among GPI deficiencies and extend the spectrum of phenotypes associated with GPI biosynthesis defects.

Glycosylphosphatidylinositols , Mandibulofacial Dysostosis , Humans , Mannosyltransferases/genetics , Mutation/genetics , Phenotype , Seizures
Cleft Palate Craniofac J ; 58(9): 1195-1200, 2021 09.
Article En | MEDLINE | ID: mdl-33349028

Rare facial clefts are characterized by facial involvement that is not restricted to the lip, palate, and alveolus as in traditional cleft lip and palate. The craniofacial skeleton and the orbital structures are frequently affected in these conditions. Exposure of the eyeball, when not early treated, puts the function and the preservation of the eye at risk. We report the case of a 2-month-old boy admitted to our service with an extensive oral-ocular cleft and exposure of the eyeball with melting corneal ulcer treated with a conjunctival closure with a purse-string suture.

Cleft Lip , Cleft Palate , Corneal Ulcer , Cleft Lip/diagnostic imaging , Cleft Lip/surgery , Cleft Palate/diagnostic imaging , Cleft Palate/surgery , Corneal Ulcer/surgery , Face , Humans , Infant , Male
J Clin Endocrinol Metab ; 105(5)2020 05 01.
Article En | MEDLINE | ID: mdl-32034419

CONTEXT: The reproductive axis is controlled by a network of gonadotropin-releasing hormone (GnRH) neurons born in the primitive nose that migrate to the hypothalamus alongside axons of the olfactory system. The observation that congenital anosmia (inability to smell) is often associated with GnRH deficiency in humans led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed. OBJECTIVE: The objective of this work is to determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures. METHODS: We conducted comprehensive phenotyping studies in 11 patients with congenital arhinia. These studies were augmented by review of medical records and study questionnaires in another 40 international patients. RESULTS: All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity. The 6 women studied in person also had apulsatile LH profiles, yet 3 had spontaneous breast development and 2 women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to 2 GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male patient. CONCLUSIONS: Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with but may not depend on olfactory structures for normal migration and function, and more broadly, illustrate the power of extreme human phenotypes in answering fundamental questions about human embryology.

Gonadotropin-Releasing Hormone/metabolism , Neurons/physiology , Nose/abnormalities , Olfaction Disorders/congenital , Abnormalities, Multiple/genetics , Abnormalities, Multiple/metabolism , Abnormalities, Multiple/pathology , Abnormalities, Multiple/physiopathology , Adolescent , Adult , Aged , Child , Child, Preschool , Cohort Studies , Female , Follicle Stimulating Hormone/blood , Gonadotropin-Releasing Hormone/deficiency , Gonads/abnormalities , Gonads/pathology , Humans , Hypogonadism/genetics , Hypogonadism/metabolism , Hypogonadism/pathology , Hypogonadism/physiopathology , Infant , Luteinizing Hormone/blood , Male , Middle Aged , Neurogenesis/physiology , Neurons/metabolism , Olfaction Disorders/genetics , Olfaction Disorders/metabolism , Olfaction Disorders/physiopathology , Olfactory Pathways/metabolism , Olfactory Pathways/pathology , Organ Size , Young Adult
Am J Med Genet A ; 179(11): 2170-2177, 2019 11.
Article En | MEDLINE | ID: mdl-31353810

Here we report on a Brazilian child who presented semilobar holoprosencephaly, frontonasal encephaloceles and bilateral cleft lip and palate. Malformations also included agenesis of the corpus callosum, abnormal cortical gyres, dilation of the aqueduct, bilateral endolymphatic sac, bilateral cystic cocci-vestibular malformation, and a cribriform defect. The 3D TC craniofacial images showed abnormal frontonasal transition region, with a bone bifurcation, and partial agenesis of nasal bone. The trunk and upper and lower limbs were normal. To our knowledge, this rare association of holoprocensephaly with frontonaso-orbital encephaloceles without limb anomalies has never been reported before. Karyotype was normal. SNP-array showed no copy-number alterations but revealed 25% of regions of homozygosity (ROH) with normal copy number, indicating a high coefficient of inbreeding, which significantly increases the risk for an autosomal recessive disorder. Whole exome sequencing analysis did not reveal any pathogenic or likely pathogenic variants. We discuss the possible influence of two variants of uncertain significance found within the patient's ROHs. First, a missense p.(Gly394Ser) in PCSK9, a gene involved in the regulation of plasma low-density lipoprotein cholesterol. Second, an inframe duplication p.(Ala75_Ala81dup) in SP8, a zinc-finger transcription factor that regulates signaling centers during craniofacial development. Further studies and/or the identification of other patients with a similar phenotype will help elucidate the genetic etiology of this complex case.

Cleft Lip/diagnosis , Cleft Lip/genetics , Cleft Palate/diagnosis , Cleft Palate/genetics , Encephalocele/diagnosis , Encephalocele/genetics , Holoprosencephaly/diagnosis , Holoprosencephaly/genetics , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Brain/abnormalities , Brain/diagnostic imaging , Chromosome Mapping , Genetic Association Studies , Genetic Predisposition to Disease , Homozygote , Humans , Imaging, Three-Dimensional , Magnetic Resonance Imaging , Male , Phenotype , Polymorphism, Single Nucleotide , Syndrome , Tomography, X-Ray Computed , Whole Exome Sequencing
Eur J Hum Genet ; 26(2): 210-219, 2018 02.
Article En | MEDLINE | ID: mdl-29348693

Blepharocheilodontic syndrome (BCDS) consists of lagophthalmia, ectropion of the lower eyelids, distichiasis, euryblepharon, cleft lip/palate and dental anomalies and has autosomal dominant inheritance with variable expression. We identified heterozygous variants in two genes of the cadherin-catenin complex, CDH1, encoding E-cadherin, and CTNND1, encoding p120 catenin delta1 in 15 of 17 BCDS index patients, as was recently described in a different publication. CDH1 plays an essential role in epithelial cell adherence; CTNND1 binds to CDH1 and controls the stability of the complex. Functional experiments in zebrafish and human cells showed that the CDH1 variants impair the cell adhesion function of the cadherin-catenin complex in a dominant-negative manner. Variants in CDH1 have been linked to familial hereditary diffuse gastric cancer and invasive lobular breast cancer; however, no cases of gastric or breast cancer have been reported in our BCDS cases. Functional experiments reported here indicated the BCDS variants comprise a distinct class of CDH1 variants. Altogether, we identified the genetic cause of BCDS enabling DNA diagnostics and counseling, in addition we describe a novel class of dominant negative CDH1 variants.

Antigens, CD/genetics , Cadherins/genetics , Catenins/genetics , Cleft Lip/genetics , Cleft Palate/genetics , Ectropion/genetics , Mutation , Tooth Abnormalities/genetics , Adolescent , Adult , Animals , Antigens, CD/metabolism , Cadherins/metabolism , Catenins/metabolism , Cell Adhesion , Child , Child, Preschool , Cleft Lip/pathology , Cleft Palate/pathology , Ectropion/pathology , Female , Humans , MCF-7 Cells , Male , Protein Binding , Tooth Abnormalities/pathology , Zebrafish
Am J Med Genet A ; 173(7): 1747-1753, 2017 Jul.
Article En | MEDLINE | ID: mdl-28558149

Mandibulofacial dysostosis (MFD) Bauru type (OMIM 604830) is a rare genetic condition characterized mainly by malar hypoplasia, orofacial cleft, and micrognathia. Here, we describe the clinical and radiographic sings of 13 individuals (12 female and 1 male) from eight unrelated kindreds with MFD Bauru type, including four previously reported cases, treated at the Hospital for Rehabilitation of Craniofacial Anomalies. The clinical phenotype was characterized by severe underdevelopment of mandible, midface hypoplasia, orofacial cleft, bitemporal narrowing, mild upper eyelid down slanting, high nasal bridge, thick and everted lower lip, minor ears abnormalities, and hearing loss. Radiographic aspects included downslanting of zygomatic arch, maxillary hypoplasia, microretrognathia, hypoplastic mandibular condyles, and ectopic external auditory canal. Recurrence was observed in two of eight families and the affected distribution pattern was compatible with autosomal dominant inheritance in one and autosomal recessive in another, indicating possible genetic heterogeneity for this condition. Clinical and radiographic findings in this report contribute to the delineation of this rare MFD.

Am J Med Genet A ; 173(4): 938-945, 2017 Apr.
Article En | MEDLINE | ID: mdl-28328130

Auriculocondylar syndrome, mainly characterized by micrognathia, small mandibular condyle, and question mark ears, is a rare disease segregating in an autosomal dominant pattern in the majority of the families reported in the literature. So far, pathogenic variants in PLCB4, GNAI3, and EDN1 have been associated with this syndrome. It is caused by a developmental abnormality of the first and second pharyngeal arches and it is associated with great inter- and intra-familial clinical variability, with some patients not presenting the typical phenotype of the syndrome. Moreover, only a few patients of each molecular subtype of Auriculocondylar syndrome have been reported and sequenced. Therefore, the spectrum of clinical and genetic variability is still not defined. In order to address these questions, we searched for alterations in PLCB4, GNAI3, and EDN1 in patients with typical Auriculocondylar syndrome (n = 3), Pierre Robin sequence-plus (n = 3), micrognathia with additional craniofacial malformations (n = 4), or non-specific auricular dysplasia (n = 1), which could represent subtypes of Auriculocondylar syndrome. We found novel pathogenic variants in PLCB4 only in two of three index patients with typical Auriculocondylar syndrome. We also performed a detailed comparative analysis of the patients presented in this study with those previously published, which showed that the pattern of auricular abnormality and full cheeks were associated with molecularly characterized individuals with Auriculocondylar syndrome. Finally, our data contribute to a better definition of a set of parameters for clinical classification that may be used as a guidance for geneticists ordering molecular testing for Auriculocondylar syndrome. © 2017 Wiley Periodicals, Inc.

Ear Diseases/diagnosis , Ear/abnormalities , Genetic Predisposition to Disease , Micrognathism/diagnosis , Mutation , Phospholipase C beta/genetics , Pierre Robin Syndrome/diagnosis , Adult , Child , Ear/pathology , Ear Diseases/classification , Ear Diseases/genetics , Ear Diseases/pathology , Endothelin-1/genetics , Female , GTP-Binding Protein alpha Subunits, Gi-Go/genetics , Gene Expression , Genes, Dominant , High-Throughput Nucleotide Sequencing , Humans , Male , Micrognathism/classification , Micrognathism/genetics , Micrognathism/pathology , Pedigree , Phenotype , Pierre Robin Syndrome/classification , Pierre Robin Syndrome/genetics , Pierre Robin Syndrome/pathology , Terminology as Topic
Mol Syndromol ; 7(6): 344-348, 2016 Nov.
Article En | MEDLINE | ID: mdl-27920638

We report on a Brazilian patient with a 1.7-Mb interstitial microdeletion in chromosome 1q21.1. The phenotypic characteristics include microcephaly, a peculiar facial gestalt, cleft lip/palate, and multiple skeletal anomalies represented by malformed phalanges, scoliosis, abnormal modeling of vertebral bodies, hip dislocation, abnormal acetabula, feet anomalies, and delayed neuropsychological development. Deletions reported in this region are clinically heterogeneous, ranging from subtle phenotypic manifestations to severe congenital heart defects and/or neurodevelopmental findings. A few genes within the deleted region are associated with congenital anomalies, mainly the RBM8A, DUF1220, and HYDIN2 paralogs. Our patient presents with a spectrum of unusual malformations of 1q21.1 deletion syndrome not reported up to date.

Clin Dysmorphol ; 24(4): 144-50, 2015 Oct.
Article En | MEDLINE | ID: mdl-25816358

Oculoauriculovertebral spectrum (OAVS, OMIM 164210) is a complex condition characterized by defects in aural, oral, and mandibular development. Other craniofacial and extracranial anomalies can be present. With the exception of the Tessier number 7 cleft, atypical clefting has rarely been reported in association with OAVS. Here, we report on two unrelated cases with a typical phenotype of OAVS and a Tessier 30 associated cleft. One of them also had other atypical facial clefts. We discuss the association between atypical facial clefts and OAVS.

Goldenhar Syndrome/diagnosis , Cleft Lip/diagnosis , Cleft Lip/pathology , Facial Bones , Goldenhar Syndrome/pathology , Humans , Infant , Male , Tomography Scanners, X-Ray Computed
J Pediatr Genet ; 2(4): 173-80, 2013 Dec.
Article En | MEDLINE | ID: mdl-27625856

The authors describe the clinical findings of 38 children with congenital anomalies and misoprostol intrauterine exposure. This study included 38 cases, ascertained from case series of the Hospital of Rehabilitation of Craniofacial Anomalies from University of São Paulo, with evidence of intrauterine exposure to misoprostol in the first trimester of the pregnancy. Information about misoprostol intake and drug administration route was obtained through interviews with mothers. Clinical evaluation showed 18 individuals with facial phenotype compatible with Moebius syndrome; 11 individuals with multiple congenital anomalies; and nine individuals with nonsyndromic cleft lip and/or cleft palate. This study showed a widening of the phenotypic spectrum associated with misoprostol embryotoxicity.