RESUMEN
Two children are presented who have a distinct syndrome of multiple buccolingual frenula, a stiff and short fifth finger with small nails, a hypothalamic hamartoma, mild to moderate neurological impairment, and mild endocrinological symptoms. No variant assessed to be pathogenic or likely pathogenic was detected in the GLI3 gene in either child. This syndrome appears to be distinct from the inherited Pallister-Hall syndrome associated with GLI3 variants, which is characterized by hypothalamic hamartoma, mesoaxial polydactyly, and other anomalies. In the individuals described here, manifestations outside of the central nervous system were milder and the mesoaxial polydactyly, which is common in individuals with Pallister-Hall syndrome, was absent. Instead, these children had multiple buccolingual frenula together with the unusual appearance of the fifth digit. It remains unclear whether these two individuals represent a separate nosologic entity or if they represent a milder manifestation of one of the more severe syndromes associated with a hypothalamic hamartoma.
Asunto(s)
Hamartoma , Enfermedades Hipotalámicas , Síndrome de Pallister-Hall , Polidactilia , Niño , Humanos , Síndrome de Pallister-Hall/diagnóstico , Síndrome de Pallister-Hall/genética , Hamartoma/diagnóstico , Hamartoma/genética , Hamartoma/patología , Enfermedades Hipotalámicas/diagnóstico , Enfermedades Hipotalámicas/genética , Enfermedades Hipotalámicas/patología , Polidactilia/genéticaRESUMEN
Pallister-Hall syndrome (PHS) is a rare autosomal dominant disease diagnosed by the presence of hypothalamic hamartoma, mesoaxial polydactyly and a truncating variant in the middle third of the GLI-Kruppel family member 3 (GLI3) gene. PHS may also include a wide range of clinical phenotypes affecting multiple organ systems including congenital anomalies of the kidney and urinary tract (CAKUT). The observed clinical phenotypes are consistent with the essential role of GLI3, a transcriptional effector in the hedgehog (Hh) signaling pathway, in organogenesis. However, the mechanisms by which truncation of GLI3 in PHS results in such a variety of clinical phenotypes with variable severity, even within the same organ, remain unclear. In this study we focus on presentation of CAKUT in PHS. A systematic analysis of reported PHS patients (n = 78) revealed a prevalence of 26.9% (21/78) of CAKUT. Hypoplasia (± dysplasia) and agenesis were the two main types of CAKUT; bilateral and unilateral CAKUT were reported with equal frequency. Examination of clinical phenotypes with CAKUT revealed a significant association between CAKUT and craniofacial defects, bifid epiglottis and a Disorder of Sex Development, specifically affecting external genitalia. Lastly, we determined that PHS patients with CAKUT predominately had substitution type variants (as opposed to deletion type variants in non-CAKUT PHS patients) in the middle third of the GLI3 gene. These results provide a foundation for future work aimed at uncovering the molecular mechanisms by which variant GLI3 result in the wide range and severity of clinical features observed in PHS.
Asunto(s)
Anomalías Múltiples , Síndrome de Pallister-Hall , Sistema Urinario , Humanos , Síndrome de Pallister-Hall/diagnóstico , Síndrome de Pallister-Hall/genética , Proteína Gli3 con Dedos de Zinc/genética , Factores de Transcripción de Tipo Kruppel/genética , Anomalías Múltiples/genética , Proteínas del Tejido Nervioso/genética , Proteínas Hedgehog , RiñónRESUMEN
Pallister-Hall syndrome, typically caused by germline or de novo variants within the GLI3 gene, has key features of hypothalamic hamartoma and polydactyly. Recently, a few similar cases have been described with bi-allelic SMO variants. We describe two siblings born to non-consanguineous unaffected parents presenting with hypothalamic hamartoma, post-axial polydactyly, microcephaly amongst other developmental anomalies. Previous clinical diagnostic exome analysis had excluded a pathogenic variant in GLI3. We performed exome sequencing re-analysis and identified bi-allelic SMO variants including a missense and synonymous variant in both affected siblings. We functionally characterised this synonymous variant showing it induces exon 8 skipping within the SMO transcript. Our results confirm bi-allelic SMO variants as an uncommon cause of Pallister-Hall syndrome and describe a novel exon-skipping mechanism, expanding the molecular architecture of this new clinico-molecular disorder.
Asunto(s)
Hamartoma , Enfermedades Hipotalámicas , Síndrome de Pallister-Hall , Polidactilia , Hamartoma/genética , Humanos , Enfermedades Hipotalámicas/diagnóstico , Enfermedades Hipotalámicas/genética , Síndrome de Pallister-Hall/diagnóstico , Síndrome de Pallister-Hall/genética , Polidactilia/genética , Receptor SmoothenedAsunto(s)
Polidactilia/diagnóstico por imagen , Ultrasonografía Prenatal , Acrocefalosindactilia/complicaciones , Acrocefalosindactilia/diagnóstico , Acrocefalosindactilia/genética , Amniocentesis , Muestra de la Vellosidad Coriónica , Trastornos de la Motilidad Ciliar/complicaciones , Trastornos de la Motilidad Ciliar/diagnóstico , Trastornos de la Motilidad Ciliar/genética , Diagnóstico Diferencial , Encefalocele/complicaciones , Encefalocele/diagnóstico , Encefalocele/genética , Femenino , Pruebas Genéticas , Humanos , Imagenología Tridimensional , Análisis por Micromatrices , Síndrome de Pallister-Hall/complicaciones , Síndrome de Pallister-Hall/diagnóstico , Síndrome de Pallister-Hall/genética , Enfermedades Renales Poliquísticas/complicaciones , Enfermedades Renales Poliquísticas/diagnóstico , Enfermedades Renales Poliquísticas/genética , Polidactilia/etiología , Embarazo , Pronóstico , Retinitis Pigmentosa/complicaciones , Retinitis Pigmentosa/diagnóstico , Retinitis Pigmentosa/genética , Distribución por Sexo , Síndrome de Smith-Lemli-Opitz/diagnóstico , Síndrome de Smith-Lemli-Opitz/genética , Síndrome de la Trisomía 13/complicaciones , Síndrome de la Trisomía 13/diagnóstico , Síndrome de la Trisomía 13/genéticaAsunto(s)
Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Trastornos de los Cromosomas/genética , Síndrome de Pallister-Hall/genética , Adulto , Trastornos de los Cromosomas/diagnóstico , Cromosomas Humanos Par 12/genética , Femenino , Humanos , Recién Nacido , Síndrome de Pallister-Hall/diagnóstico , EmbarazoRESUMEN
INTRODUCTION: Pallister-Hall syndrome (PHS) is a rare autosomal dominant syndrome characterized by polydactyly, bifid or shortened epiglottis, visceral anomalies, hypothalamic hamartoma often combined with hypopituitarism. PHS is characterized by significant variability in the expression of clinical symptoms. The clinical course ranges from mild with a good prognosis to severe and which can lead to death during the neonatal period. CASE REPORT: Two-years-old girl with facial dysmorphia, skeletal malformations of hand and feet and growth hormone deficiency. PHS was diagnosed on the basis of the presented symptoms and genetic tests. SUMMARY: Skeletal malformations, such as polydactyly or oligodactyly, are a markers which can be associated with endocrinological disorders. Quick and correct diagnosis would help in planning treatment during childhood and giving family counseling, including prenatal advice regarding the next pregnancy of the child's mother.
Asunto(s)
Síndrome de Pallister-Hall/diagnóstico , Preescolar , Femenino , Humanos , Síndrome de Pallister-Hall/genética , Síndrome de Pallister-Hall/terapiaRESUMEN
Pallister-Hall syndrome (PHS) is a rare malformative disorder that is due to truncating functional repressor mutations in GLI3. Since the seminal publication in 1980, hypothalamic tumors have been recognized to be a cardinal feature of PHS. In their original description of the neuropathologic features of PHS, Clarren et al. coined the term "hamartoblastoma" to characterize what they deemed to be a dual malformative and neoplastic mass of the hypothalamus. In subsequent published cases/series of PHS, the term "hamartoma" was often substituted for hamartoblastoma given what appeared to be a benign natural history of this lesion. Additional confusion in the literature has ensued since most hypothalamic hamartomas (HH) encountered on the clinical neuropathology service are "isolated" in nature (ie, no other congenital malformations) and present in a very different and stereotypical fashion with gelastic seizures and/or precocious puberty. While genomic investigations of isolated HH have begun to uncover a mutational profile of these cases, GLI3 mutations have only been recognized in a small subset of isolated HH. Herein, we describe the autopsy findings from a 21-week gestational age fetus with features of PHS. Moreover, we provide a detailed description of the hypothalamic tumor affecting this fetus and propose a novel subclassification of HH, distinguishing syndromic from isolated forms based upon the presence or absence of neocortical-like areas.
Asunto(s)
Síndrome de Pallister-Hall/patología , Terminología como Asunto , Aborto Eugénico , Adulto , Autopsia , Femenino , Humanos , Masculino , Síndrome de Pallister-Hall/diagnósticoRESUMEN
Pallister Hall syndrome is autosomal dominant disorder usually diagnosed in infants and children. Current diagnostic criteria include presence of hypothalamic hamartoma, post axial polydactyly and positive family history, but the disease has variable manifestations. Herein we report Pallister Hall syndrome diagnosed in a family where both patients were adults. A 59 year old man developed seizures 4 years prior to our evaluation of him, at which time imaging showed a hypothalamic hamartoma. The seizures were controlled medically. He did well until he had visual changes after a traumatic head injury. Repeat MRI showed slight expansion of the mass with formal visual field testing demonstrating bitemporal hemianopsia. There was no evidence of pituitary dysfunction except for large urine volume. He underwent surgery to debulk the hamartoma and the visual field defects improved. There was no hypopituitarism post-operatively, and the polydyspia resolved. His 29 year old daughter also had seizures and hypothalamic hamartoma. Both patients had had polydactyly with prior surgical correction in childhood. The daughter underwent genetic testing, which revealed a previously undescribed heterozygous single base pair deletion in exon 13 of the GLI3 gene causing a frameshift mutation. Further investigation into family history revealed multiple members in previous generations with polydactyly and/or seizures. Pallister-Hall syndrome is caused by an inherited autosomal dominant or de novo mutation in GLI3 gene. This rare syndrome has not had prevalence defined, however. Generally, diagnoses are made in the pediatric population. Our report adds to the few cases detected in adulthood.
Asunto(s)
Mutación del Sistema de Lectura , Proteínas del Tejido Nervioso/genética , Síndrome de Pallister-Hall/diagnóstico , Proteína Gli3 con Dedos de Zinc/genética , Adulto , Análisis Mutacional de ADN , Diagnóstico Tardío , Familia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndrome de Pallister-Hall/genéticaRESUMEN
Pallister-Hall syndrome was initially recognized under fairly unique circumstances involving exhumation of the very first case. The first two cases had dramatic and unusual features including a hypothalamic hamartoblastoma, imperforate anus, an unusual type of polydactyly with the extra digit being central, hypopituitarism with secondary hypoadrenalism, and lethality after birth (probably due to hypoadrenalism). Within a short time frame, four additional cases were identified. As the full spectrum and variability of anomalies was recognized, it became clear that it was not such a rare disorder. Shortly after familial cases were recognized, the responsible gene was identified at GLI3. However, since other different conditions also involved GLI3, elaborating the domains of the gene and the types of mutations needed to be defined in order to have a clear correlation of the genotype-phenotype relations.
Asunto(s)
Factores de Transcripción de Tipo Kruppel/genética , Mutación , Proteínas del Tejido Nervioso/genética , Síndrome de Pallister-Hall/genética , Síndrome de Pallister-Hall/historia , Autopsia , Exhumación , Expresión Génica , Genes Letales , Estudios de Asociación Genética , Historia del Siglo XX , Humanos , Recién Nacido , Masculino , Síndrome de Pallister-Hall/diagnóstico , Síndrome de Pallister-Hall/patología , Proteína Gli3 con Dedos de ZincRESUMEN
Polydactyly is among comnion extremity abnormalities. Mutations of GLI3 gene have been reported commonly in Greig Cephalopolysyndactyly Syndrome (GCPS) and Pallister-Hall Syndrome (PHS). We have determined two different mutations of GLI3 gene in two different cases, one of which is with GCPS and the other one is with PHS. A deletion mutation was detected in the proband with GCPS and his mother. Otherwise, we found that, unlike the previously reported, the mutation c.2437C>T, p.Q813X which was detected in the GLI3 gene caused typical PHS. We are in thought of that our cases will contribute to understanding of phenotypic variability leading to GLI3 mutations.
Asunto(s)
Acrocefalosindactilia/genética , Análisis Mutacional de ADN , Síndrome de Pallister-Hall/genética , Proteína Gli3 con Dedos de Zinc/genética , Acrocefalosindactilia/diagnóstico , Adolescente , Ano Imperforado/diagnóstico , Ano Imperforado/genética , Variación Biológica Poblacional , Niño , Tamización de Portadores Genéticos , Asesoramiento Genético , Hamartoma/diagnóstico , Hamartoma/genética , Humanos , Imagen por Resonancia Magnética , Masculino , Síndrome de Pallister-Hall/diagnóstico , Enfermedades de la Hipófisis/diagnóstico , Enfermedades de la Hipófisis/genética , Eliminación de Secuencia/genéticaAsunto(s)
Hamartoma/diagnóstico , Enfermedades Hipotalámicas/diagnóstico , Síndrome de Pallister-Hall/diagnóstico , Ano Imperforado/etiología , Preescolar , Enanismo/etiología , Femenino , Hamartoma/etiología , Humanos , Enfermedades Hipotalámicas/etiología , Imagen por Resonancia Magnética , Neuroimagen/métodos , Neurología/educación , Síndrome de Pallister-Hall/complicaciones , Polidactilia/etiologíaRESUMEN
Pallister-Hall syndrome is a complex malformation syndrome characterized by a wide range of anomalies including hypothalamic hamartoma, polydactyly, bifid epiglottis, and genitourinary abnormalities. It is usually caused by truncating frameshift/nonsense and splicing mutations in the middle third of GLI3. The clinical course ranges from mild to lethal in the neonatal period. We present the first patient with Pallister-Hall syndrome reported with total colonic aganglionosis, a rare form of Hirschsprung disease with poor long-term outcome. The patient also had an imperforate anus, which is the third individual with Pallister-Hall syndrome reported with both Hirschsprung disease and an imperforate anus. Molecular testing via amniocentesis showed an apparently de novo novel nonsense mutation c.2641 C>T (p.Gln881*). His overall medical course was difficult and was complicated by respiratory failure and pan-hypopituitarism. Invasive care was ultimately withdrawn, and the patient expired at three months of age. This patient's phenotype was complex with unusual gastrointestinal features ultimately leading to a unfavorable prognosis and outcome, highlighting the range of clinical severity in patients with Pallister-Hall syndrome.
Asunto(s)
Ano Imperforado/diagnóstico , Ano Imperforado/genética , Enfermedad de Hirschsprung/diagnóstico , Enfermedad de Hirschsprung/genética , Síndrome de Pallister-Hall/diagnóstico , Síndrome de Pallister-Hall/genética , Ano Imperforado/cirugía , Biopsia , Hibridación Genómica Comparativa , Resultado Fatal , Femenino , Enfermedad de Hirschsprung/cirugía , Humanos , Recién Nacido , Cariotipo , Factores de Transcripción de Tipo Kruppel/genética , Mutación , Proteínas del Tejido Nervioso/genética , Fenotipo , Embarazo , Índice de Severidad de la Enfermedad , Tomografía Computarizada por Rayos X , Ultrasonografía Prenatal , Proteína Gli3 con Dedos de ZincRESUMEN
The Pallister-Hall syndrome (PHS) was identified and described as a specific entity in the late 1970s and early 1980s. Subsequently, many patients were reported expanding the phenotype. Familial cases demonstrated variability and lead to linkage and then gene identification. Mutations in the responsible gene, GLI3 are also known to be involved in several other disorders. Genotype/phenotype correlations have led to fine mapping of GLI3 and the recognition that PHS is caused by dominant negative mutations in the middle third of the gene.
Asunto(s)
Genética Médica , Síndrome de Pallister-Hall/diagnóstico , Síndrome de Pallister-Hall/genética , Genética Médica/historia , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Síndrome de Pallister-Hall/historiaAsunto(s)
Hamartoma/patología , Enfermedades Hipotalámicas/patología , Síndrome de Pallister-Hall/patología , Determinación de la Edad por el Esqueleto , Preescolar , Diagnóstico Diferencial , Pie/diagnóstico por imagen , Hamartoma/diagnóstico , Hamartoma/diagnóstico por imagen , Mano/inervación , Humanos , Enfermedades Hipotalámicas/diagnóstico , Enfermedades Hipotalámicas/diagnóstico por imagen , Extremidad Inferior/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Síndrome de Pallister-Hall/diagnóstico , Síndrome de Pallister-Hall/diagnóstico por imagen , PronósticoRESUMEN
Pallister-Hall syndrome (PHS) is a rare condition characterised by anomalies including hypothalamic hamartoma, bifid epiglottis and postaxial polydactyly. Hearing loss has been recognised in this condition. Cochlear abnormalities have been described in mouse models of PHS, but there are no reports of similar findings in humans to date. This report describes a case of PHS with bilateral cochlear hypoplasia as seen on MRI.
Asunto(s)
Cóclea/anomalías , Cóclea/patología , Pérdida Auditiva Sensorineural/diagnóstico , Imagen por Resonancia Magnética/métodos , Síndrome de Pallister-Hall/diagnóstico , Femenino , Humanos , Lactante , Recién NacidoRESUMEN
Pallister-Hall syndrome (PHS) is a pleiotropic autosomal-dominant malformation syndrome rarely presenting with genitourinary malformations. Literature has recorded 14 cases of PHS with genitourinary findings out of which only six have been females presenting with hydrometrocolpos and/or vaginal atresia. Fetal autopsy findings on a 39 weeks' gestation including demonstration of corticotroph deficiency in the pituitary, along with the review of literature is being presented here. None of the earlier literature pertaining to PHS with hydrometrocolpos and/or vaginal atresia describes an intrauterine fetal demise due to corticotroph deficiency.
Asunto(s)
Muerte Fetal , Síndrome de Pallister-Hall/diagnóstico , Síndrome de Pallister-Hall/patología , Adulto , Autopsia , Femenino , Humanos , Recién Nacido , EmbarazoRESUMEN
We describe two patients with Pallister-Hall syndrome (PHS) with genital abnormalities: a female with hydrometrocolpos secondary to vaginal atresia and a male with micropenis, hypoplastic scrotum, and bilateral cryptorchidism. Nonsense mutations in GLI3 were identified in both patients. Clinical and molecular findings of 12 previously reported patients who had GLI3 mutations and genital abnormalities were reviewed. Genital features in the male patients included hypospadias, micropenis, and bifid or hypoplastic scrotum, whereas all the females had hydrometrocolpos and/or vaginal atresia. No hotspot for GLI3 mutations has been found. The urogenital and anorectal abnormalities associated with PHS might be related to dysregulation of SHH signaling caused by GLI3 mutations rather than hormonal aberrations. We recommend that clinical investigations of genital abnormalities are considered in patients with PHS, even those without hypopituitarism.
Asunto(s)
Anomalías Múltiples/genética , Síndrome de Pallister-Hall/diagnóstico , Anomalías Urogenitales/diagnóstico , Anomalías Urogenitales/genética , Niño , Preescolar , Codón sin Sentido , ADN/genética , ADN/aislamiento & purificación , Exones , Femenino , Mutación del Sistema de Lectura , Genes Dominantes , Heterocigoto , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Masculino , Proteínas del Tejido Nervioso/genética , Técnicas de Amplificación de Ácido Nucleico , Reacción en Cadena de la Polimerasa , Proteína Gli3 con Dedos de ZincRESUMEN
BACKGROUND: Bifid epiglottis is a congenital malformation defined as a midline-cleft of the epiglottis, which can be presented as an isolated anomaly as well as a part of malformation complexes. Its common occurrence in Pallister-Hall syndrome (PHS) has recently been attracting special attention. In the embryo, epiglottis, hypothalamus, and digital buds develop synchronously. Some disturbances during this stage may account for the concurrence of bifid epiglottis, hypothalamic hamartoma, and polysyndactyly in PHS. The incidence of bifid epiglottis remains unknown. METHODS: We report here four children with bifid epiglottis out of 472 children who underwent laryngoscopy during the period from January 1995 to December 2004 in our hospital. RESULTS: All four children presented stridor of variable degrees. One had a partial cleft of the epiglottis associated with only tracheomalacia. The other three had a complete cleft of the epiglottis associated with complex malformations: one had accessory auricles with preauricular sinus, polycystic kidney disease with intrahepatic biliary dilatation, endocardial cushion defect, and postaxial polydactyly; another had hypothalamic hamartoma, Hirschsprung disease, and polydactyly, which warranted a diagnosis of PHS; the other had no other dysmorphic features. CONCLUSION: Bifid epiglottis can be presented as a syndromic constituent of congenital malformation syndromes rather than as an isolated anomaly. A high index of suspicion of bifid epiglottis should be raised in children with brachy-poly-syndactyly and clinical symptoms of upper airway obstruction.