Bifid Epiglottis Research Articles

SOMATIC MUTATIONS IN GLI3 CAN CAUSE HYPOTHALAMIC HAMARTOMA AND GELASTIC SEIZURES

Hypothalamic hamartomas are congenital mass lesions consisting of mature neuronal and glial elements that resemble normal gray matter. They are usually sporadic but rarely are associated with Pallister–Hall syndrome (PHS), an autosomal dominant syndrome with additional congenital anomalies including insertional polydactyly, imperforate anus, and bifid epiglottis. PHS is due to mutations in the zinc-finger transcription factor gene GLI3 on chromosome 7p13.1 GLI proteins are involved in downstream regulation of sonic hedgehog-mediated CNS development, where they are the key regulators of target-gene expression.2 Hypothalamic hamartomas are associated with the remarkable phenomenon of gelastic (laughing) seizures often accompanied by a severe and medically refractory epilepsy syndrome. The lesions causing epilepsy are typically in the third ventricle and were previously regarded as inoperable. The development of a safe and effective transcallosal technique to remove these epileptogenic lesions3 allowed us to test the hypothesis that sporadic hypothalamic hamartomas were associated with somatic GLI3 mutations. ### Methods. We obtained hypothalamic hamartoma tissue samples from 15 patients operated on at the Royal Children's Hospital in Melbourne, Australia. All had refractory epilepsy and none had a family history or clinical features of …

Bifid epiglottis revisited

Bifid epiglottis is an extremely rare congenital laryngeal anomaly which has been increasingly associated with genetic syndromes. The true bifid epiglottis has been distinguished in the past from an epiglottis that is notched or has a submucous cleft, as the latter was not felt to be related to other congenital anomalies. Presented are two cases of bifid epiglottis, one with a complete cleft, and one with a submucous cleft; both children had associated abnormalities. The implications of bifid epiglottis and associated syndromes are discussed.

Clefting of the Epiglottis — Rare, but Usually Syndromic

Clefting of the epiglottis, or bifid epiglottis, is a relatively rare abnormality that is almost always associated with several other congenital

Significance of bifid epiglottis

Bifid epiglottis is a rare anomaly, which is heterogeneous and is often associated with other anomalies, particularly polydactyly. It has been reported in 40% of patients with Pallister-Hall syndrome and rarely in other syndromes. We report two brothers with bifid epiglottis who also have features suggestive of Bardet-Biedl syndrome. We also review the features seen in 22 patients reported in the literature with bifid epiglottis. No patient had bifid epiglottis as an isolated anomaly. Other malformations include clefts, micropenis, renal abnormalities, anal malformations, hypospadias, hypothalamic hamartomas, hypopituitarism, heart defects, and Hirschprung disease. Bifid epiglottis may be an under-recognized feature of Bardet-Biedl syndrome and should be considered in these patients, particularly if there are airway symptoms. Many of the anomalies associated with bifid epiglottis have potentially serious consequences and thus, a thorough evaluation of the patient with bifid epiglottis is warranted.

Psychiatric and neuropsychological characterization of Pallister‐Hall syndrome

Pallister-Hall syndrome (PHS) is a rare, single-gene, malformation syndrome that includes central polydactyly, hypothalamic hamartoma, bifid epiglottis, endocrine dysfunction, and other anomalies. The syndrome has variable clinical manifestations and is inherited in an autosomal dominant pattern. We sought to determine whether psychiatric disorders and/or neuropsychological impairment were characteristic of PHS. We prospectively conducted systematic neuropsychiatric evaluations with 19 PHS subjects ranging in age from 7 to 75 years. The evaluation included detailed clinical interviews, clinician-rated and self-report instruments, and a battery of neuropsychological tests. Seven of 14 adult PHS subjects met diagnostic criteria for at least one DSM-IV Axis I disorder. Three additional subjects demonstrated developmental delays and/or neuropsychological deficits on formal neuropsychological testing. However, we found no characteristic psychiatric phenotype associated with PHS, and the frequency of each of the diagnoses observed in these subjects was not different from that expected in this size sample. The overall frequency of psychiatric findings among all patients with PHS cannot be compared to point prevalence estimates of psychiatric disease in the general population because of biased ascertainment. This limitation is inherent to the study of behavioral phenotypes in rare disorders. The general issue of psychiatric evaluation of rare genetic syndromes is discussed in light of this negative result.

Gonadal mosaicism in severe Pallister-Hall syndrome.

Pallister-Hall syndrome (PHS, MIM #146510) is characterized by central and postaxial polydactyly, hypothalamic hamartoma (HH), bifid epiglottis, imperforate anus, renal abnormalities, and pulmonary segmentation anomalies. It is inherited in an autosomal dominant pattern. Here, we describe a family with two affected children manifesting severe PHS with mental retardation, behavioral problems, and intractable seizures. Both parents are healthy, with normal intelligence, and have no malformations on physical, laryngoscopic, and cranial MRI exam. The atypical presentation of these children and the absence of parental manifestations suggested an autosomal recessive mode of inheritance or gonadal mosaicism. Sequencing of GLI3 revealed a two nucleotide deletion in exon 15 (c.3385_3386delTT) predicting a frameshift and premature stop at codon 1129 (p.F1129X) in the children while both parents have wild type alleles. Genotyping with GLI3 intragenic markers revealed that both children inherited the abnormal allele from their mother thus supporting gonadal mosaicism as the underlying mechanism of inheritance (paternity was confirmed). This is the first reported case of gonadal mosaicism in PHS. The severe CNS manifestations of these children are reminiscent of children with non-syndromic HH who often have progressive mental retardation with behavioral problems and intractable seizures. We conclude that the phenotypic spectrum of PHS can include severe CNS manifestations and that recurrence risks for PHS should include a proviso for gonadal mosaicism, though the frequency cannot be calculated from a single case report. Published 2003 Wiley-Liss, Inc.

A novel loss-of-function mutation in TTF-2 is associated with congenital hypothyroidism, thyroid agenesis and cleft palate

Thyroid dysgenesis is the most common cause of congenital hypothyroidism (CH) and its genetic basis is largely unknown. Here, we describe the second homozygous missense mutation in TTF-2 (or FOXE1), a transcription factor that has been implicated in thyroid development. Two male siblings, born to consanguineous parents, presented with CH, athyreosis and cleft palate and were found to be homozygous for a mutation corresponding to a serine to asparagine substitution at codon 57 (S57N) in the forkhead DNA binding domain of TTF-2. Their heterozygous parents were unaffected and this mutation was not found in 31 unrelated cases of athyreosis or normal controls. Consistent with its location, the S57N TTF-2 mutant protein showed impaired DNA binding and partial loss of transcriptional function. Such incomplete loss of TTF-2 function may account for the absence of choanal atresia and bifid epiglottis in our patients, anomalies which were present together with CH and cleft palate in two other individuals with the only other, more deleterious, TTF-2 mutation (A65V) described previously. Our observations support the role of TTF-2 in both thyroid and palate development but suggest phenotypic heterogeneity of this syndromic form of CH.

Evidence for decreased growth hormone in patients with hypothalamic hamartoma due to Pallister-Hall syndrome.

Pallister-Hall syndrome (PHS) is characterized by hypothalamic hamartoma, bifid epiglottis, and central or postaxial polydactyly. Familial transmission is autosomal dominant; isolated cases also occur. To screen for hypothalamic-pituitary dysfunction in PHS, we studied a 12 year-old boy (patient #1), and 14 additional patients (patients #2-14: 7M, 7F; ages 4-72 yr). We performed serial sampling of GH, LH/FSH, TSH, and cortisol from 20.00-08 00 h. At 08.00 h, we measured IGF-I, peak responses of LH and FSH after GnRH, and cortisol after ACTH. We found that 6/7 children, including patient #1, and 6/8 adults had low or absent spontaneous GH secretion and/or low levels of IGF-I. Patient #1 also had accelerated pubertal development, but no other patient had abnormalities of the pituitary-gonadal axis, and none of the 14 patients had an abnormal thyroid or adrenal axis. We conclude that decreased pituitary GH secretion is common in PHS, and may exist in the absence of other forms of endocrine dysfunction.

Asymptomatic laryngeal malformations are common in patients with Pallister-Hall syndrome.

Pallister-Hall syndrome (PHS) comprises hypothalamic hamartoma, polydactyly, pituitary dysfunction, laryngotracheal cleft, imperforate anus, and other anomalies. Some patients with PHS have a bifid epiglottis, a rare malformation. Greig cephalopolysyndactyly syndrome (GCPS) comprises polydactyly with craniofacial malformations without the PHS malformations. Both disorders are caused by mutations in the GLI3 gene. Laryngoscopy on 26 subjects with PHS showed that 15 had a bifid or cleft epiglottis (58%) and none of 14 subjects with GCPS had a cleft epiglottis. The malformed epiglottis was asymptomatic in all of the prospectively evaluated subjects. One additional PHS subject was found to have bifid epiglottis and a posterior laryngeal cleft on autopsy. We conclude that bifid epiglottis is common in PHS but not GCPS. Posterior laryngeal clefts are an uncommon manifestation of PHS and are identified only in severely affected patients. The diagnosis of a bifid epiglottis should prompt a thorough search for other sometimes asymptomatic anomalies of PHS to provide better medical care and recurrence risk assessment for affected individuals and families.

Otolaryngologic features of Laurence-Moon–Bardet-Biedl syndrome

The most common otolaryngologic features associated with LMBBS include SNHL, speech and language disorders, and oral and dental abnormalities. Early otolaryngologic, audiologic, speech pathology, and dental evaluation of these individuals is recommended. This is the first reported case of bifid epiglottis, a rare congenital laryngeal anomaly, found in association with LMBBS. Most patients with bifid epiglottis have additional congenital anomalies, most commonly polysyndactyly. Polysyndactyly is a feature of both LMBBS and bifid epiglottis and may be an early hallmark for the presence of other congenital anomalies.

A new syndrome: Heart defects, laryngeal anomalies, preaxial polydactyly, and colonic aganglionosis in sibs

We present two siblings, one male and one female, who have heart defects, duplicat~on of toes, airway anomalies, and aganglionosis. The brother also has a bilateral complete cleft lip and palate. H i s airway anomalies lnclude short epiglottis and aryepiglottic folds, which are different from his sister who has a bifid epiglottis with a central epiglottic mass. Both siblings have had some developmental delay. This constellation of anomalies appears to be unique and may represent a new autosomal recessive disorder.

Bifid epiglottis

Bifid epiglottis is a rare congenital defect that is often associated with other congenital annomalies. The most common defect associated with a bifid epiglottis are anomalies of the hands and/or feet (90%) while the most dangerous and potentially lethal anomaly if not recognized and treated are hypothalamic hamartomas and hypopituitarism (50%). A bifid epiglottis will often result in severe respiratory distress secondary to laxity of the cartilage and chronic aspirations, which may require surgical intervention. We present the case of a 10-week-old child who was sent for evaluation of stridor and aspiration. Office laryngoscopy demonstrated a true bifid epiglottis and further evaluation demonstrated a hypothalamic hamartoma consistent with Pallister–Hall syndrome. Management of our case as well as those previously presented in the literature are reviewed.

Bifid Epiglottis

The true bifid epiglottis is a rare congenital anomaly typically discovered during the evaluation of stridor in an infant or newborn. While it is not classified as a specific syndrome, there are frequent associations of other congenital anomalies with the bifid epiglottis. These include midline defects (such as microphallus, hypospadius, imperforate anus, and midline laryngeal cleft), endocrine disorders (including congenital hypopituitarism), and central nervous system neoplasms, including hypothalamic hamartoblastoma. The embryogenesis and options for surgical management of this anomaly are reviewed, and one case is presented in detail.

Bifid epiglottis syndrome

True bifid epiglottis is an extremely rare laryngeal anomaly, which usually presents in the neonate with symptoms of aspiration and/or airway obstruction. Management is generally supportive observation as the symptoms lessen with age, but rarely tracheotomy is required for airway obstruction. Bifid epiglottis occurs in a syndromic picture with associated anomalies, especially polydactyly, cleft palate and retro/micrognathia but a significant number will have endocrine, gastrointestinal and genitourinary abnormalities. A case of true bifid epiglottis is presented and the literature is reviewed on the subject.

Bifid epiglottis: a case report

Bifid epiglottis is a rare congenital laryngeal anomaly, usually associated with multiple congenital anomalies which include digital anomalies and hypothalamic pituitary dysfunction manifesting as growth retardation. A case is presented of a 2-year-old child with this picture in whom the bifid epiglottis prolapsed over the laryngeal inlet to cause inspiratory airway obstruction. Corrective surgery was not successful and eventually a partial epiglottectomy was required.

A cluster of Pallister-Hall syndrome cases, (congenital hypothalamic hamartoblastoma syndrome)

We report on three infants with hand anomalies and congenital hypopituitarism. In two of the cases, a hypothalamic tumor was found; the third infant died without postmortem brain studies. Family history in the first case suggested possible familial recurrence; the mother's sister had died at 17 hr of age with polydactyly, microglossia, and flat nasal bridge (no autopsy done). Our second case was born by cesarean section after a pregnancy complicated by extremely low maternal estriols. At birth, hypopituitarism was diagnosed, a cranial CT scan was read as normal, and hormonal replacement was begun with thyroxine, hydrocortisone, and growth hormone. At 11.5 mo of age she developed seizures; and a repeat CT scan showed a mass extending beneath the hypothalamus. This tumor was removed surgically at 12 mo, the first successful treatment of this disorder. Our third possible case had a bifid epiglottis, hypopituitarism, and hand anomalies. A CT scan at birth failed to reveal a mass in the hypothalamus. This child died from complications of untreated hypopituitarism, and no neuropathology studies were done. These three cases were conceived between March 10th and April 17th in three different years in three geographically contiguous counties of Vermont. Clustering in time and space and possible familial recurrence, in one of these cases, suggest a possible gene/environment interaction.

1287 SYNDROMES ASSOCIATED WITH POLYDACTYLY AND HYPOPITUITARISM

We report two female infants with postaxial polydactyly and hypopituitarism of differing etiologies. The first infant was born at term to a 26-year-old gravida 6 para 2 abortus 4 woman who noted markedly decreased fetal movement and intrauterine growth retardation. She was delivered from a breech presentation with posteriorly rotated simplified auricles, short nose, flat nasal bridge, microglossia, micrognathia, cleft posterior palate, short limbs with dislocated hips, postaxial polydactyly of hands and feet, bilateral simian creases, and 2-3 syndactyly of the toes. She died at 21 hours of age and autopsy revealed hypothalamic hamartoblastoma, bilateral hypoplastic renal ectopia, bilateral pulmonary hypoplasia, and a bifid epiglottis. Family history revealed that the mother's sister had died at 17 hours of age with remarkably similar dysmorphic features (no autopsy done), and this is the first report of apparent familial recurrence for Hall-Pallister syndrome. The second infant was born by cesarean section at 42 weeks with postaxial polydactyly of the left hand and primary panhypopituitarism. This pregnancy in a 21-year-old gravida 2, abortus 1 woman was complicated by extremely low maternal estriols. Size at birth and a cranial CT scan were normal, and the family history was negative for other individuals with hypopituitarism or polydactyly. Postaxial polydactyly may be associated with hypopituitarism, especially when associated with cleft palate, choanal atresia, congenital heart disease, and basal brain anomalies.

Bifid epiglottis: A rare laryngeal anomaly

Two cases of bifid epiglottis are presented: one with an associated laryngeal cyst and another with an associated cricoid stenosis. The occurrence of multiple laryngeal anomalies in association with bifid epiglottis has not previously been described. The occurrence of an extra digit is noted to be statistically significant both in the current series and in a review of the literature. A brief review of the embryologic classification and staging by the Carnegie System, and the correlation of the time sequence of development of the epiglottis is presented. No correlation is made as to the mechanism of the origin of this laryngeal anomaly, as adequate embryologic knowledge of the development of the pharynx is not available at this time.

Bifid epiglottis. Report of a case.

A case of bifid epiglottis is reported in which the main symptom was aspiration with feeding, which lessened with age as the epiglottis halves became more rigid. This case differs from a prior case report in which the symptoms were those of laryngeal obstruction, necessitating a tracheostomy and eventual amputation of the epiglottis for cure. The embryology of the epiglottis is discussed.