Clinical and molecular heterogeneity of syndromic hypothalamic hamartoma.

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.

[Analysis of variant of GLI3 gene in a child featuring autosomal dominant Pallister-Hall syndrome].

OBJECTIVE: To explore the clinical and genetic characteristics of a child with Pallister-Hall syndrome (PHS). METHODS: DNA was extracted from peripheral blood sample from the child and subjected to whole exome sequencing. Suspected variants were verified by Sanger sequencing of his family members. RESULTS: Genetic testing revealed that the child has harbored a heterozygous c.3320_3330delGGTACGAGCAG (p.G1107Afs×18) variant of the GLI3 gene. Neither parent was found to carry the same variant. CONCLUSION: The c.3320_3330delGGTACGAGCAG (p.G1107Afs×18) frameshift variant of the GLI3 gene probably underlay the pathogenesis of PHS in this child. Genetic testing should be considered for patients featuring hypothalamic hamartoma and central polydactyly.

Analysis of variant of GLI3 gene in a child featuring autosomal dominant Pallister-Hall syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical and genetic characteristics of a child with Pallister-Hall syndrome (PHS).@*METHODS@#DNA was extracted from peripheral blood sample from the child and subjected to whole exome sequencing. Suspected variants were verified by Sanger sequencing of his family members.@*RESULTS@#Genetic testing revealed that the child has harbored a heterozygous c.3320_3330delGGTACGAGCAG (p.G1107Afs×18) variant of the GLI3 gene. Neither parent was found to carry the same variant.@*CONCLUSION@#The c.3320_3330delGGTACGAGCAG (p.G1107Afs×18) frameshift variant of the GLI3 gene probably underlay the pathogenesis of PHS in this child. Genetic testing should be considered for patients featuring hypothalamic hamartoma and central polydactyly.

Pallister-Hall syndrome, GLI3, and kidney malformation.

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.

Neuroimaging appearance of hypothalamic hamartomas in monozygotic twins with Pallister-Hall syndrome: case report and review of the literature.

BACKGROUND: Pallister-Hall syndrome (OMIM #146510) is a rare autosomal dominant condition caused by a mutation in the GLI3 gene. The cardinal feature of Pallister-Hall syndrome is the presence of hypothalamic hamartomas, which may manifest with seizures, panhypopituitarism and visual impairment. In Pallister-Hall syndrome, dysplastic histogenetic processes responsible for hypothalamic hamartomas are thought to disrupt early craniofacial development. The clinical presentation of Pallister-Hall syndrome may include: characteristic facies (low-set and posteriorly angulated ears, short nose with flat nasal bridge), cleft palate and uvula, bifid epiglottis and laryngotracheal cleft, limb anomalies (e.g., polysyndactyly, short limbs and nail dysplasia), anal atresia, genitourinary abnormalities and congenital heart defects. CASE PRESENTATION: We report the case of two monochorionic diamniotic twins diagnosed with Pallister-Hall syndrome during the neonatal period, after the identification of a hypothalamic hamartoma on day 1 by cerebral ultrasound scan, later confirmed by brain magnetic resonance imaging. Cerebral ultrasound and magnetic resonance imaging presentations were identical in both twins. DISCUSSION AND CONCLUSIONS: We review previously published cases (four reports) of hypothalamic hamartomas identified via cerebral ultrasound and compare reported ultrasonographic features. Main differential diagnoses based on cerebral ultrasound findings are discussed. Full description of typical magnetic resonance imaging appearance is also provided. This is the first case reported in the literature of monochorionic diamniotic twins affected by genetically confirmed Pallister-Hall syndrome with identical hypothalamic hamartomas at cerebral ultrasound and magnetic resonance imaging. Moreover, this paper adds to the existing literature on the sonographic appearance of hypothalamic hamartomas. Considering the consistency in hypothalamic hamartomas' sonographic appearance, we support the use of cerebral ultrasound as a first-line neuroimaging modality in case of clinical suspicion of Pallister-Hall syndrome.

Bi-allelic SMO variants in hypothalamic hamartoma: a recessive cause of Pallister-Hall syndrome.

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.

A GLI3 variant leading to polydactyly in heterozygotes and Pallister-Hall-like syndrome in a homozygote.

Variants in transcriptional activator Gli Kruppel Family Member 3 (GLI3) have been reported to be associated with several phenotypes including Greig cephalopolysyndactyly syndrome (MIM #175700), Pallister-Hall syndrome (PHS) (MIM #146510), postaxial polydactyly types A1 (PAPA1) and B (PAPB) (MIM #174200), and preaxial polydactyly type 4 (MIM #174700). All these disorders follow an autosomal dominant pattern of inheritance. Hypothalamic hamartomas (MIM 241800) is associated with somatic variants in GLI3. We report a related couple with parents having PAPA1 and PAPB, who had a fetus with a phenotype most compatible with PHS. Molecular analyses demonstrated homozygosity for a pathogenic GLI3 variant (c.1927C > T; p. Arg643*) in the fetus and heterozygosity in the parents. The genetic analysis in this family demonstrates that heterozygosity and homozygosity for the same GLI3 variant can cause a different phenotype. Furthermore, the occurrence of Pallister-Hall-like syndrome in a homozygous patient should be taken into account in genetic counseling of families with PAPA1/PAPB.

Genetic factors in isolated and syndromic laryngeal cleft.

A laryngotracheoesophageal cleft (LC) is a rare congenital anomaly of the upper aerodigestive tract resulting from the absence of fusion of the posterior cricoid lamina, which affects an abnormal communication between the larynx, trachea and esophagus. The genetic etiology of LC remains elusive. The involvement of genetic factors in the development of LC is suggested by reports of familial occurrence, and the increased prevalence of component features among first-degree relatives of affected individuals and murine knockout models. No consistent pattern of inheritance has been found in nonsyndromic patients, except for cases associated with described syndromes. Once the syndrome related to the laryngeal cleft is considered, an active search for the cleft must be initiated. The genetic evaluation of patients with LCs should be guided by the type and location of the malformation, specific medical history and a detailed physical examination. The application of genetic approaches, such as microarrays and exome sequencing might lead to elucidating the etiology of LCs.

Pallister-Hall syndrome in a 2-years-old girl.

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.

Novel GLI3 variant causing overlapped Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS) phenotype with agenesis of gallbladder and pancreas.

BACKGROUND: A proper balance between the activator and the repressor form of GLI3, a zinc-finger transcription factor downstream of hedgehog signaling, is essential for proper development of various organs during development. Mutations in different domains of the GLI3 gene underlie several congenital diseases including Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS). CASE PRESENTATION: Here, we describe the case of an overlapped phenotype of these syndromes with agenesis of the gallbladder and the pancreas, bearing a c.2155 C > T novel likely pathogenic variant of GLI3 gene by missense point mutation causing p.P719S at the proteolytic cleavage site. CONCLUSIONS: Although agenesis of the gallbladder and the pancreas is uncommon in GLI3 morphopathy, a slight difference in the gradient or the balance between activator and repressor in this case may hinder sophisticated spatial and sequential hedgehog signaling that is essential for proper development of gallbladder and pancreas from endodermal buds.

Familial Pallister-Hall in adulthood.

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.

Compound heterozygous alterations in intraflagellar transport protein CLUAP1 in a child with a novel Joubert and oral-facial-digital overlap syndrome.

Disruption of normal ciliary function results in a range of diseases collectively referred to as ciliopathies. Here we report a child with a phenotype that overlapped with Joubert, oral-facial-digital, and Pallister-Hall syndromes including brain, limb, and craniofacial anomalies. We performed exome-sequence analysis on a proband and both parents, filtered for putative causative variants, and Sanger-verified variants of interest. Identified variants in CLUAP1 were functionally analyzed in a Xenopus system to determine their effect on ciliary function. Two variants in CLUAP1 were identified through exome-sequence analysis, Chr16:g.3558407T>G, c.338T>G, p.(Met113Arg) and Chr16:g.3570011C>T, c.688C>T, p.(Arg230Ter). These variants were rare in the Exome Aggregation Consortium (ExAC) data set of 65,000 individuals (one and two occurrences, respectively). Transfection of mutant CLUAP1 constructs into Xenopus embryos showed reduced protein levels p.(Arg230Ter) and reduced intraflagellar transport p.(Met113Arg). The genetic data show that these variants are present in an affected child, are rare in the population, and result in reduced, but not absent, intraflagellar transport. We conclude that biallelic mutations in CLUAP1 resulted in this novel ciliopathy syndrome in the proband.

The early history of Pallister-Hall syndrome-Buried treasure of a sort.

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.

TWO DIFFERENT MUTATIONS OF GL13 GENE IN TWO DIFFERENT SYNDROMES.

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.

Urogenital development in Pallister-Hall syndrome is disrupted in a cell-lineage-specific manner by constitutive expression of GLI3 repressor.

Pallister-Hall syndrome (PHS) is a rare disorder caused by mutations in GLI3 that produce a transcriptional repressor (GLI3R). Individuals with PHS present with a variably penetrant variety of urogenital system malformations, including renal aplasia or hypoplasia, hydroureter, hydronephrosis or a common urogenital sinus. The embryologic mechanisms controlled by GLI3R that result in these pathologic phenotypes are undefined. We demonstrate that germline expression of GLI3R causes renal hypoplasia, associated with decreased nephron number, and hydroureter and hydronephrosis, caused by blind-ending ureters. Mice with obligate GLI3R expression also displayed duplication of the ureters that was caused by aberrant common nephric duct patterning and ureteric stalk outgrowth. These developmental abnormalities are associated with suppressed Hedgehog signaling activity in the cloaca and adjacent vesicular mesenchyme. Mice with conditional expression of GLI3R were utilized to identify lineage-specific effects of GLI3R. In the ureteric bud, GLI3R expression decreased branching morphogenesis. In Six2-positive nephrogenic progenitors, GLI3R decreased progenitor cell proliferation reducing the number of nephrogenic precursor structures. Using mutant mice with Gli3R and Gli3 null alleles, we demonstrate that urogenital system patterning and development is controlled by the levels of GLI3R and not by an absence of full-length GLI3. We conclude that the urogenital system phenotypes observed in PHS are caused by GLI3R-dependent perturbations in nephric duct patterning, renal branching morphogenesis and nephrogenic progenitor self-renewal.

Total colonic aganglionosis and imperforate anus in a severely affected infant with Pallister-Hall syndrome.

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.

Pallister-Hall syndrome has gone the way of modern medical genetics.

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.

Presentación de tres casos de síndrome de Pallister-Killian / Three cases of Pallister-Killian syndrome

Introducción. El síndrome de Pallister-Killian se caracteriza por discapacidad intelectual, hipotonía, retraso motor y un fenotipo característico en el que destaca un aspecto facial tosco, alteraciones pigmentarias de la piel y alopecia bitemporal. Es frecuente que se asocie a crisis convulsivas y a malformaciones en otros órganos y sistemas. Tiene como causa principal el mosaicismo para la tetrasomía del cromosoma 12p. Casos clínicos. Se presentan tres nuevos casos pediátricos afectos de esta rara entidad, se describen las características clínicas y se realiza una revisión de la bibliografía. Conclusiones. Debe resaltarse la importancia del conocimiento del síndrome para poder llevar a cabo su diagnóstico, puesto que lo habitual es que, sin practicar la biopsia cutánea o el frotis de mucosa bucal, la anomalía cromosómica pasa desapercibida si se usan técnicas citogenéticas clásicas. Hoy en día, es posible realizar el diagnóstico en sangre mediante array-CGH o array-SNP, si bien la posibilidad de encontrar la anomalía cromosómica depende del porcentaje de mosaicismo (AU)

Introduction. Pallister-Killian syndrome is characterised by intellectual disability, hypotonia, motor disability and a characteristic phenotype in which notable features include a rugged-looking face, alterations affecting the pigmentation of the skin and bitemporal alopecia. It is often associated with seizures and malformations in other organs and systems. The main cause is mosaicism for tetrasomy of chromosome 12p. Case reports. We present three new paediatric cases of this rare entity, its clinical features are described and a literature review is carried out. Conclusions. It is important to be familiar with the syndrome so that it can be diagnosed, since what commonly happens is that, without performing a skin biopsy or buccal smear, the chromosomal abnormality goes undetected if the classic cytogenetic techniques are used. Nowadays, the diagnosis can be performed in blood by means of CGH-array or SNP-array, although the chances of finding the chromosomal anomaly depend on the percentage of mosaicism (AU)