Pallister-Hall syndrome is a pleiotropic autosomal dominant disorder comprising hypothalamic hamartoma, pituitary dysfunction, central polydactyly, and visceral malformations (Biesecker et al., 1996).
Iafolla et al. (1989) pointed out that magnetic resonance imaging is the most valuable diagnostic tool; CT scan has been reported to miss the tumor.
An international workshop on Pallister-Hall syndrome (Biesecker et al., 1996) developed ... Iafolla et al. (1989) pointed out that magnetic resonance imaging is the most valuable diagnostic tool; CT scan has been reported to miss the tumor. An international workshop on Pallister-Hall syndrome (Biesecker et al., 1996) developed minimal diagnostic criteria for this entity. The index case in a family must have both hypothalamic hamartoma and central polydactyly to meet the diagnostic criteria. First-degree relatives of the index case must have either hypothalamic hamartoma or polydactyly (central or postaxial) and show inheritance in an autosomal dominant pattern or in a manner consistent with gonadal mosaicism. Recommendations for clinical evaluation of suspected cases were presented. Biesecker et al. (1996) concluded that hypothalamic hamartoma is not specific to PHS. - Prenatal Diagnosis Sills et al. (1993) reported Pallister-Hall syndrome in a male infant and his female sib fetus. Sills et al. (1994) reported that the parents elected to terminate their third pregnancy because prenatal ultrasonographic findings suggested PHS. At 12 weeks, ultrasound demonstrated an abnormal-appearing fetus with large head and a large midline anterior fluid-filled structure, possibly representing a dilated, malformed ventricle. Repeat examination at 13 weeks showed evidence of holoprosencephaly, enlarged cisterna magna, short umbilical cord, polydactyly, and possible syndactyly. The limbs appeared short. At termination at 15 weeks, chromosome studies of chorionic villus cells showed a normal 46,XX karyotype. - Differential Diagnosis Verloes et al. (1992) commented that 'Some years ago, syndromologists and clinical geneticists were pleasantly divided into splitters...and lumpers...' With the increasing volume of reported congenital anomalies, they suggested that 2 new categories may be delineated: the 'stretchers,' who are mainly preoccupied with extending the limits of a given phenotype by adding milder or unusually severe variants, and the 'cut-and-pasters,' who displace the same atypical or borderline cases from one syndrome to another. Verloes et al. (1992) reviewed the differential diagnosis of Pallister-Hall syndrome and of syndromal hypothalamic hamartoblastoma in general. The conditions that they considered as related included Smith-Lemli-Opitz syndrome (270400), the pseudotrisomy 13 syndrome or holoprosencephaly-polydactyly syndrome (264480), orofaciodigital syndrome type VI or Varadi-Papp syndrome (277170), and the hydrolethalus syndrome (236680). Because of the insolvable overlap, Verloes et al. (1992) suggested the creation of a phenotypic classification called the multiplex syndrome, defined as a clinical frame encompassing an unknown number of genetic and/or nongenetic multiple congenital anomaly (MCA) syndromes, for which differential diagnosis cannot be performed unequivocally. They suggested calling this the cerebroacrovisceral early lethality (CAVE) multiplex syndrome. Verloes et al. (1995) described a 24-week-old fetus with agenesis of the corpus callosum, arhinencephaly, hypothalamic hamartoblastoma, absence of the right thumb, hypoplastic left thumb, hypoplastic lungs, intestinal malrotation, microgastria, asplenia, 'inverted' horseshoe kidney, blind vagina, and absence of internal genitalia. Underdevelopment of preaxial structures had not previously been reported in the Pallister-Hall syndrome, in which postaxial polydactyly is a cardinal feature. Although some features suggested the 'microgastria-limb reduction' complex (156810), patients with that complex are usually not so severely affected and have never had associated hypothalamic hamartoblastoma. Donnai et al. (1987) had suggested that the Pallister-Hall syndrome and severe Smith-Lemli-Opitz syndrome (270400) are the same disorder. Using multivariate analysis and numerical taxonomy, Verloes et al. (1995) concluded that on review, 'most overlapping cases (and, in fact, most cases reported as Pallister-Hall, including some from the original report)' could be unambiguously classified as Smith-Lemli-Opitz syndrome, orofaciodigital syndrome type VI (277170), or holoprosencephaly-polydactyly syndrome (264480). Together with the absence of anomalies of cholesterol metabolism, a combination of oral frenula, laryngeal malformations, digestive abnormalities, intercalary polysyndactyly, generalized brachytelephalangism, and nail hypoplasia should allow the delineation of Pallister-Hall syndrome, even when a CNS tumor is absent (Verloes, 1995). The radiologic abnormalities in the hand are helpful in differentiating Pallister-Hall syndrome from other syndromes in which hypothalamic hamartoblastoma is observed. This may be of major importance for genetic counseling because Pallister-Hall syndrome is an autosomal dominant disorder, whereas most most of the other disorders with the CAVE phenotype are recessively inherited. Because of a possible relationship of PHS to Smith-Lemli-Opitz syndrome, Biesecker et al. (1996) analyzed levels of cholesterol and intermediate metabolites of the later stages of cholesterol biosynthesis and found no evidence of a generalized disorder of cholesterol biosynthesis in patients with familial PHS. On genetic and biochemical grounds, they concluded that PHS and Smith-Lemli-Opitz syndrome are not allelic variants of a single locus. Unsinn et al. (1995) described a patient who had hydrocolpos and postaxial polydactyly as well as hypothalamic hamartoblastoma, raising the possibility that the Pallister-Hall syndrome and the McKusick-Kaufman syndrome (MKKS; 236700) are one entity. Lurie (1995) questioned whether the Kaufmann-McKusick syndrome and the Pallister-Hall syndrome can be considered one entity. Lurie and Wulfsberg (1994) found in a survey of 43 reported familial cases of MKKS neither preaxial nor central forms of polydactyly. Lurie (1995) stated that he also did not remember vaginourethral fistula as occurring in these patients. Kang et al. (1997) noted that large deletions or translocations resulting in haploinsufficiency of the GLI3 gene have been associated with Greig cephalopolysyndactyly syndrome (GCPS; 175700), which maps to the same region of chromosome 7p, although no mutations in GLI3 were identified in GCPS patients with normal karyotypes. Both PHS and GCPS have polysyndactyly and abnormal craniofacial features and are inherited in an autosomal dominant pattern, but are clinically distinct. The polydactyly of GCPS is commonly preaxial and that of PHS is typically central or postaxial. No reported cases of GCPS had hypothalamic hamartoma and PHS does not cause hypertelorism or broadening of the nasal root or forehead. Some patients with PHS have a bifid epiglottis, a rare malformation. On laryngoscopy in 26 subjects with PHS, Ondrey et al. (2000) found that 15 had a bifid or cleft epiglottis (58%); of 14 subjects with GCPS, which is also caused by mutation in the GLI3 gene, no instance of cleft epiglottis was found. 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. Ondrey et al. (2000) concluded that bifid epiglottis is common in PHS, whereas posterior laryngeal clefts are uncommon and occur only in severely affected patients. They suggested that 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.
Hall et al. (1980) reported 6 infants with a neonatally lethal malformation syndrome of hypothalamic hamartoblastoma, postaxial polydactyly, and imperforate anus. Some had laryngeal cleft, abnormal lung lobation, renal agenesis or dysplasia, short fourth metacarpals, nail dysplasia, multiple ... Hall et al. (1980) reported 6 infants with a neonatally lethal malformation syndrome of hypothalamic hamartoblastoma, postaxial polydactyly, and imperforate anus. Some had laryngeal cleft, abnormal lung lobation, renal agenesis or dysplasia, short fourth metacarpals, nail dysplasia, multiple buccal frenula, hypoadrenalism, microphallus, congenital heart defect, and intrauterine growth retardation. All cases were sporadic and chromosomes were apparently normal. The parents were nonconsanguineous. No environmental exposure was common to all cases. The ages of the fathers were 21, 25, 25, 29, 43, and unknown. The anterior pituitary was not found in any patient. The hypothalamic tumor was apparent on the inferior surface of the cerebrum and extended from the optic chiasma to the interpeduncular fossa. The tumor replaced the hypothalamus and other nuclei that originate in the embryonic hypothalamic plate. It was composed mainly of cells resembling primitive, undifferentiated germinal cells. Graham et al. (1983) described an infant with abnormal auricles, short nose with flattened bridge, microglossia, micrognathia, cleft palate, short limbs, dislocated hips, and 4-limb postaxial polydactyly. The infant died at 2 hours of age and autopsy showed hypothalamic hamartoblastoma. A sister of the mother died at 17 hours of age and showed 4-limb polydactyly, recessed mandible, and small tongue; autopsy was not done. See 241800. Iafolla et al. (1989) reported that nail dysplasia accompanies the postaxial polydactyly. Pallister et al. (1989) described 3 additional cases. One patient had imperforate anus and right hydronephrosis and hydroureter with absent left kidney; another had imperforate anus without the renal anomalies. A teratogen had been suspected because of the fact that cases were not recognized before February 1978. Pallister et al. (1989) suggested, however, that autopsy of cases of imperforate anus with associated CNS lesions should be reviewed. Finnigan et al. (1991) described 2 unrelated patients with the usual features of Pallister-Hall syndrome, including diencephalic anomalies, but without hamartoblastomas. Topf et al. (1993) reported affected father and son. The 9-year-old son had precocious puberty, imperforate anus, postaxial polydactyly, hypospadias, a hypothalamic mass, and a displaced pituitary gland; his 34-year-old father had polydactyly, a hypothalamic mass, and a flattened pituitary gland. In the son imperforate anus, postaxial polydactyly, and hypospadias, were surgically corrected early in life. His subsequent growth and development were normal. He had minor craniofacial dysmorphism. At the age of 8 years, he presented because of precocious puberty and was found by MRI scan to have a large hypothalamic mass and displaced pituitary. The father's polydactyly consisted of an accessory digit, apparently originating from the third metacarpal. His facial features resembled those of the son. He did not have a history of imperforate anus or hypospadias. Penman Splitt et al. (1994) also reported an instance of male-to-male transmission: a 9-year-old boy had hamartoblastoma, midaxial and postaxial polydactyly with brachydactyly, hypospadias, imperforate anus, and precocious puberty. The 34-year-old father had central and postaxial polydactyly, macrocephaly, and a hypothalamic mass. Both were of normal intelligence. Thomas et al. (1994) reported a definite sib recurrence of Pallister-Hall syndrome in a family without a cytogenetically visible chromosome abnormality. The father of the 2 affected sibs was born with nearly identical digital abnormalities and could represent either mild expression or mosaicism for a dominant gene. The first-born infant, a female, was noted at birth to have choanal atresia, bifid epiglottis, and cleft upper larynx with posterior web in the subglottic area. Her nose was short, with depressed nasal bridge and anteverted nares. There was bilateral hexadactyly with osseous 2/3 syndactyly of the right hand that was thought to represent an insertional type of polydactyly. Subsequently she developed signs of hypopituitarism, had recurrent problems with upper airway obstruction eventually necessitating tracheostomy, and required gastrostomy because of feeding difficulties. She died at 12 months of age after a respiratory infection. At necropsy, a tracheal diverticulum and abnormal lobation of the lungs were found. The pituitary gland was absent with a rudimentary stalk. A 2 x 2 cm soft nodular mass completely replaced the hypothalamus. The male sib was born at 30 weeks' gestation and required respiratory support after birth for upper airway obstruction. He had 4/5 syndactyly of the right hand with postaxial polydactyly of both hands and short fourth and fifth digits. He also had micropenis. Laryngoscopy and bronchoscopy showed a bifid uvula and epiglottis with cleft larynx. He subsequently was shown to have hypopituitarism and a cerebral MRI scan showed a 2 x 2 cm mass in the hypothalamic region with signal characteristics identical to those of normal brain tissue. He died suddenly at 9.5 months of age after a respiratory infection. The father was born with nearly complete 4/5 cutaneous syndactyly of the right hand and postaxial polydactyly of both hands. He had no other abnormalities. Both parents also had normal chromosomes. Sama et al. (1994) reported an affected newborn female with a large suprasellar mass with a posterior cystic component, bilateral choanal atresia, renal hypoplasia, exomphalos, postaxial polydactyly, and underdevelopment of the 4th metacarpal. Her father was 38 years old. Verloes et al. (1995) reported the cases of 2 unrelated, long surviving patients, aged 2 and 17 years, with Pallister-Hall syndrome. In addition to hypothalamic hamartoblastoma, both showed mild facial dysmorphism (downward slanted palpebral fissures, ptosis, microretrognathia), cleft epiglottis, and developmental delay. The younger child had stenosis of the pulmonary arteries, complex urogenital malformations, and anal atresia. The older patient had precocious puberty caused by the hamartoma, combined with complete growth hormone deficiency. Both patients showed bony anomalies of the limbs: variable proximal synostosis between the second to fourth metacarpals or intercalary polydactyly with generalized brachydactyly, severe brachytelephalangism, syndactyly, and nail hypoplasia. The range of phenotypic variability in the Pallister-Hall syndrome may be demonstrated by the mother and son reported by Low et al. (1995). A 53-year-old woman and her 20-year-old son both presented with polysyndactyly but without other external malformations or mental retardation. MRI revealed, as an incidental finding, asymptomatic hypothalamic hamartomas in both patients. The sibs of both the mother and the son were unaffected. Kang et al. (1997) described the clinical characteristics of a family with a mild form of PHS. Clinical, radiographic, and endoscopic evaluations showed that the disorder was fully penetrant with variable expressivity and low morbidity. The proband was a 21-month-old child who was noted to have ptosis and polydactyly at the time of birth. Cranial MRI showed a hypothalamic mass compatible with hamartoma. The family history showed that she had 21 relatives with polydactyly in an autosomal dominant pattern. The pedigree included 9 obligate heterozygotes, all of whom had some manifestation of the disorder. The ratio of males to females was 6 to 16. Several members of the family had central polydactyly (also referred to as mesoaxial or insertional polydactyly). This form typically includes partial osseous syndactyly with proximal fusion of the metacarpals and is characteristic of only a few syndromes. Galasso et al. (2001) described a boy with Pallister-Hall syndrome with short stature and growth hormone neurosecretory dysfunction. The patient was found to have deficient spontaneous growth hormone secretion despite a normal response to pharmacologic stimulation. The patient responded positively to long-term growth hormone treatment. Galasso et al. (2001) concluded that growth hormone deficiency should be considered a cause of short stature in patients with Pallister-Hall syndrome, especially when their growth rates decrease.
Johnston et al. (2005) hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause Pallister-Hall syndrome, whereas haploinsufficiency of GLI3 cause Greig cephalopolysyndactyly syndrome (GCPS; 175700). To test this hypothesis, they screened 46 patients with PHS ... Johnston et al. (2005) hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause Pallister-Hall syndrome, whereas haploinsufficiency of GLI3 cause Greig cephalopolysyndactyly syndrome (GCPS; 175700). To test this hypothesis, they screened 46 patients with PHS and 89 patients with GCPS for GLI3 mutations. They detected 47 pathologic mutations (among 60 probands), and when these mutations were combined with previously published mutations, 2 genotype-phenotype correlations were evident. GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations. In contrast, PHS was caused only by frameshift/nonsense and splicing mutations. Among the frameshift/nonsense mutations, Johnston et al. (2005) found a clear genotype/phenotype correlation. Mutations in the first third of the gene (from open reading frame nucleotides 1-1997) caused GCPS, and mutations in the second third of the gene (from nucleotides 1998-3481) caused primarily PHS. Surprisingly, there were 12 mutations in patients with GCPS in the 3-prime third of the gene (after open reading frame nucleotide 3481), and no patients with PHS had mutations in this region. These results demonstrated a robust genotype/phenotype correlation for GLI3 mutations and strongly supported the hypothesis that these 2 allelic disorders have distinct modes of pathogenesis. Narumi et al. (2010) reported 2 Japanese patients, a 3-year-old girl and a 10-year-old boy, with PHS and genital anomalies, both of whom had heterozygous nonsense mutations in the GLI3 gene. The authors reviewed the 12 previously reported patients with PHS and genital anomalies, all of whom had nonsense or frameshift mutations in exons 13, 14, or 15 of GLI3; however, no hotspot for GLI3 mutations was found. In affected males, hypospadias was observed in 3 patients, micropenis in 2, and bifid or hypoplastic scrotum in 2. Three also had an anorectal abnormality (imperforate anus) and 1 had a urologic abnormality (small kidney). In affected females, all had hydrometrocolpos and/or vaginal atresia; 2 also had an anorectal abnormality (imperforate anus and rectoperineal fistula), and 4 had various urologic abnormalities, including vesicoureteral reflux in 2. Some of these patients had affected family members with anorectal anomalies and/or rectovaginal fistula, but no genital abnormalities. Narumi et al. (2010) concluded that genital features in PHS patients might present a wide range of severity even among individuals with the same nucleotide change. Noting that none of the female patients and only 2 of the male patients had panhypopituitarism, the authors suggested that the urogenital and anorectal abnormalities might be related to dysregulation of SHH (600725) signaling rather than hormonal aberrations.
Because of the colocalization of the loci for PHS and GCPS, Kang et al. (1997) investigated GLI3 as a candidate gene for PHS. They reported 2 PHS families with frameshift mutations in GLI3 (165240.0002; 165240.0003) located 3-prime of ... Because of the colocalization of the loci for PHS and GCPS, Kang et al. (1997) investigated GLI3 as a candidate gene for PHS. They reported 2 PHS families with frameshift mutations in GLI3 (165240.0002; 165240.0003) located 3-prime of the zinc finger-encoding domains, including 1 family with a de novo mutation. Killoran et al. (2000) reported a family in which the proposita was born with central polydactyly of the right hand, broad thumbs, and short fingers with hypoplastic nails. She also had a small right kidney, imperforate anus, and a hypoplastic iliac bone. An older sib with renal agenesis and polydactyly had died. The mother had polydactyly and imperforate anus. A maternal aunt had polydactyly, as did the maternal grandfather. Molecular analysis of the proposita identified a mutation in the GLI3 gene (165240.0017). The authors noted that subsequent clinical data showed that the patient had a hypothalamic hamartoma. This finding and the molecular analysis led to the diagnosis of PHS. Killoran et al. (2000) stated that they had originally diagnosed their patient with PIV (polydactyly, imperforate anus, and vertebral anomalies) syndrome as defined by Say and Gerald (1968). They doubted that the PIV designation was still useful and suggested that it be viewed as a historic antecedent to the VACTER/VACTERL association (192350). Stoll et al. (2001) described a patient considered to have Pallister-Hall syndrome in whom they could not identify a mutation in the GLI3 gene. The patient had microphallus and no growth hormone deficiency. He had presented with postaxial polydactyly of the hands, dysplastic nails, imperforate anus, small penis, scrotum bifidum with very thin urethra, bifid epiglottis, and a bilateral simian crease. There was vesicoureteral reflux, insertional hexadactyly of the left hand, and 2 Y-shaped metacarpals with 6 fingers in the right hand. Brain MRI revealed a large sellar and suprasellar mass. Bronchoscopy showed anterior synechia of the vocal cords with cricoid stenosis. A tracheostomy was performed. Mental development was normal. In an erratum, the authors stated that they had identified a missense mutation in exon 13 of the GLI1 gene in this patient.
Pallister-Hall syndrome (PHS) can be diagnosed based on clinical findings in individuals with classic signs. Molecular genetic testing may be useful to confirm the diagnosis in these individuals and is used to establish the diagnosis in individuals in whom the clinical findings are ambiguous or mild. ...
DiagnosisPallister-Hall syndrome (PHS) can be diagnosed based on clinical findings in individuals with classic signs. Molecular genetic testing may be useful to confirm the diagnosis in these individuals and is used to establish the diagnosis in individuals in whom the clinical findings are ambiguous or mild. Clinical DiagnosisMajor findings are the following: Hypothalamic hamartoma, a non-enhancing mass in the floor of the third ventricle posterior to the optic chiasm that is isointense to grey matter on T1 and T2 pulse sequences of an MRI, but may have distinct intensity on FLAIR (Neither cranial CT examination nor cranial ultrasound examination is adequate for diagnosis of hypothalamic hamartoma.)Mesoaxial (i.e., insertional or central) polydactyly, the presence of six or more well-formed digits with a 'Y'-shaped metacarpal or metatarsal bonePostaxial polydactyly (PAP) types A and B. PAP-A is the presence of a well-formed digit on the ulnar or fibular aspect of the limb. PAP-B is the presence of a rudimentary digit or nubbin in the same location. Postaxial polydactyly is probably more common than mesoaxial polydactyly; however, the nonspecificity of postaxial polydactyly and the high frequency of postaxial polydactyly type B in persons of central African descent require caution in its use as a diagnostic feature. Bifid epiglottis, a midline anterior-posterior cleft of the epiglottis that involves at least two thirds of the epiglottic leaf. It is a useful feature for clinical diagnosis because it appears to be very rare in syndromes other than PHS and is also rare as an isolated malformation. Other. Imperforate anus, renal abnormalities including cystic malformations, renal hypoplasia, ectopic ureteral implantation, genitourinary anomalies including hydrometrocolpos, pulmonary segmentation anomalies including bilateral bilobed lungs, and non-polydactyly skeletal anomalies including short limbsThe diagnosis is established in the following individuals:A proband if mesoaxial polydactyly and hypothalamic hamartoma are present The first-degree relative of a proband if hypothalamic hamartoma or central or postaxial polydactyly are present (Postaxial polydactyly type B can be used as a diagnostic criterion for first-degree relatives only in persons who are not of central African descent.) Individuals with postaxial (but not mesoaxial) polydactyly and a hypothalamic hamartoma or mesoaxial polydactyly without hypothalamic hamartoma or hypothalamic hamartoma and other non-polydactyly malformations should be considered for GLI3 sequencing.Note: The phenotyping issues for persons with atypical phenotypes and GLI3 mutations are complex and beyond the scope of this review.Molecular Genetic TestingGene. GLI3 is the only gene in which mutations are known to cause Pallister-Hall syndrome. Clinical testingSee Table 3 (pdf) for selected pathologic alleles. Table 1. Summary of Molecular Genetic Testing Used in Pallister-Hall SyndromeView in own windowGeneTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityGLI3Sequence analysis / mutation scanning of select exons 2Sequence variants in the selected exons 3See footnote 4Clinical Sequence analysis Sequence variants 3~95%Deletion / duplication analysis 5Exonic or whole-gene deletions / duplicationsUnknown, none reported 61. The ability of the test method used to detect a mutation that is present in the indicated gene2. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably among laboratories depending on the specific protocol used.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; 4. Mutations in a panel and the detection frequency vary by laboratory.5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. 6. Typically, exonic or whole-gene deletions/duplications are not detected in individuals with Pallister-Hall syndrome (though deletions may be present in individuals with Greig cephalopolysyndactyly syndrome).Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a proband. Molecular genetic testing may be useful to confirm the diagnosis in individuals who meet clinical criteria and to establish the diagnosis in individuals in whom the clinical findings are ambiguous or mild. Mutation scanning of select exons or sequence analysis of the entire gene should be pursued first.Deletion/duplication analysis for GLI3 is an option; however, exonic or whole-gene deletions/duplications would not be expected to lead to Pallister-Hall syndrome (see Genotype-Phenotype Correlations)Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation in the family. Genetically Related (Allelic) DisordersOther phenotypes are associated with mutations in GLI3:Greig cephalopolysyndactyly syndrome (GCPS) includes polydactyly that is commonly preaxial and may also be postaxial. The polydactyly is commonly associated with cutaneous syndactyly. GCPS has craniofacial features that include widely spaced eyes, broad forehead, and macrocephaly. Mesoaxial polydactyly and osseous syndactyly of the metacarpals are not part of GCPS. Most individuals with GCPS have mutations that cause haploinsufficiency of GLI3, although a few individuals with a point mutation have been described. However, it has not been demonstrated that these point mutations have stable mRNA or protein. If the stability of these molecules were reduced, the point mutations would result in functional haploinsufficiency. At least one individual with preaxial polydactyly type IV (PPDIV) has been reported to have a GLI3 mutation [Radhakrishna et al 1999] — a finding consistent with clinical suspicion that PPDIV is a mild form of GCPS, in which the limb findings occur without the craniofacial features. However, the craniofacial findings are subtle and controversy exists as to the distinction of nonsyndromic PPDIV from mild GCPS [Biesecker 2006]. Isolated postaxial polydactyly type A (PAP-A). Mutations in GLI3 have been identified in individuals with PAP-A [Radhakrishna et al 1999]. However, the PAP-A phenotype has also been shown to result from mutations in other genes. Isolated preaxial polydactyly type IV (PPDIV) comprises preaxial polydactyly of the hands and/or feet in the absence of other malformations. The severity of the PPDIV is highly variable [Everman 2006]. Because macrocephaly occurs in the general population and is common in GCPS, the presence of macrocephaly in a person with apparently isolated PPDIV is difficult to interpret. Sub-PHS is a descriptor applied to individuals who have features of PHS, but do not meet the clinical criteria for diagnosis of PHS. The clinical criteria for sub-PHS: One of the following:Mesoaxial polydactylyHypothalamic hamartomaOligodactylyPostaxial polydactyly AND One of the following: Bifid epiglottisImperforate anusSmall nailsHypopituitarismGrowth hormone deficiencyGenital hypoplasia In one study, 40% (8/20) of affected persons had mutations in GLI3 that were similar to the mutations in individuals with PHS [Johnston et al 2010].Sub-GCPS is a descriptor applied to individuals who have features of GCPS, but do not meet clinical criteria for a diagnosis of GCPS. The clinical criteria for sub-GCPS: One of the following:Preaxial polydactylyBroad thumbs or great toesCutaneous syndactylyMacrocephalyWidely spaced eyes OR Both of the following:Postaxial polydactylyHypoplasia of the corpus callosumIn a recent study, 29% (8/28) of individuals who met these criteria had mutations in GLI3 [Johnston et al 2010].Oral-facial-digital overlap syndrome is a descriptor used for individuals who have features that overlap with OFD and PHS. The criteria for this disorder:Polydactyly AND One of the following:Oral frenulaOral hamartomaCleft lipCleft palateCerebellar vermis hypoplasiaTibial hypoplasiaIn a recent study, 29% (6/21) individuals in this category had a mutation in GLI3 [Johnston et al 2010].
Pallister-Hall syndrome (PHS) displays a wide range of severity. The literature frequently reflects the assumption that PHS is severe and Greig cephalopolysyndactyly syndrome is mild. This is clearly incorrect, as a minority of individuals with PHS show multiple severe anomalies and most individuals with PHS are mildly affected with polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma. Without careful clinical evaluation, these individuals may be incorrectly diagnosed with PAP-A. ...
Natural HistoryPallister-Hall syndrome (PHS) displays a wide range of severity. The literature frequently reflects the assumption that PHS is severe and Greig cephalopolysyndactyly syndrome is mild. This is clearly incorrect, as a minority of individuals with PHS show multiple severe anomalies and most individuals with PHS are mildly affected with polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma. Without careful clinical evaluation, these individuals may be incorrectly diagnosed with PAP-A. The prognosis for an individual with PHS and no known family history of PHS is based on the malformations present in the individual. Literature surveys are not useful for the purpose of establishing the prognosis because reported cases tend to show bias of ascertainment to more severe involvement. Although PHS has been categorized as a member of the CAVE (cerebroacrovisceral early lethality) group of disorders, few affected individuals have an early lethality phenotype. This early lethality is most likely attributable to panhypopituitarism that is caused by pituitary or hypothalamic dysplasia or severe airway malformations such as laryngotracheal clefts. In addition, imperforate anus can cause serious complications if not recognized promptly. Thus, in the absence of life-threatening malformations, the prognosis should be assumed to be excellent for individuals with the nonfamilial occurrence of PHS. For individuals with a family history of affected family members, the prognosis is based on the degree of severity present in the family. Hypothalamic hamartoma. Hypothalamic hamartoma is a malformation, not a tumor. Hypothalamic hamartomas grow at the rate of, or slower than, the surrounding brain tissue. Hypothalamic hamartomas may be large (up to 4 cm in greatest dimension); little correlation exists between the size of the hypothalamic hamartoma and presence or severity of symptoms. Individuals with hypothalamic hamartomas may have neurologic symptoms, although most are asymptomatic. Removal of the hypothalamic hamartoma is not indicated and often results in iatrogenic pituitary insufficiency. Neurologic findings. The best-described neurologic complication of hypothalamic hamartoma is gelastic epilepsy, a partial complex seizure manifest by clonic movements of the chest and diaphragm that simulate laughing. Other types of seizures may be caused by hypothalamic hamartoma. Seizures associated with hypothalamic hamartoma in individuals with PHS are generally milder and are responsive to treatment, in contrast to individuals with nonsyndromic hypothalamic hamartoma who often have refractory seizures [Boudreau et al 2005]. No individual with PHS has been shown to have visual field loss even with a hypothalamic hamartoma near the optic chiasm. Psychiatric and neuropsychological findings. Some individuals with PHS have behavioral manifestations including a few with severe intellectual disability and behavioral disturbances [Ng et al 2004]. A larger study of behavioral manifestations of this disorder was inconclusive, reflecting the difficulty of assessing mild behavioral phenotypes in rare disorders [Azzam et al 2005]. Endocrine manifestations. The endocrine manifestations of a hypothalamic hamartoma range from isolated growth hormone deficiency or isolated precocious puberty to panhypopituitarism, which can be life threatening. Cortisol deficiency can occur in nonfamilial cases, but appears to be rare in familial cases. Epiglottic abnormalities. Bifid epiglottis is nearly always asymptomatic; however, the more severe clefts of the larynx reported in individuals with PHS can cause severe airway symptoms. Posterior laryngeal clefts can be fatal.
Genotype-phenotype correlations of GLI3 mutations ...
Genotype-Phenotype CorrelationsGenotype-phenotype correlations of GLI3 mutations GCPS is caused by the following: Actual or functional haploinsufficiency for GLI3 Truncating mutations within and 5' of the zinc finger domains and in the 3'-most third of the gene PHS is generally caused by truncating mutations in the middle third of the gene [Johnston et al 2005].
Differential DiagnosisCentral polydactyly Oral-facial-digital syndrome type 6 includes central polydactyly with hypoplasia of the cerebellar vermis. Renal agenesis and dysplasia have been described. Holzgreve syndrome (central polydactyly, cleft palate, heart defect) Postaxial polydactyly McKusick-Kaufman syndrome (MKS) is characterized by the triad of hydrometrocolpos in females and genital malformations in males, postaxial polydactyly (PAP) or central polydactyly, and congenital heart disease (CHD). Mutations in MKKS have been found in individuals with MKS within the Amish population. Inheritance is autosomal recessive. Holt-Oram syndrome (HOS) is characterized by upper-extremity malformations involving radial, thenar, or carpal bones and a personal and/or family history of congenital heart malformation, most commonly ostium secundum atrial septal defect (ASD) and ventricular septal defect (VSD), especially those occurring in the muscular trabeculated septum and/or cardiac conduction disease. TBX5 is the only gene currently known to be associated with HOS. TBX5 mutations are found in more than 70% of individuals with HOS. Inheritance is autosomal dominant. Bardet-Biedl syndrome is characterized by rod-cone dystrophy, truncal obesity, postaxial or central polydactyly, cognitive impairment, male hypogonadotrophic hypogonadism, complex female genitourinary malformations, and renal dysfunction, which is a major cause of morbidity and mortality. Fourteen genes are known to be associated with Bardet-Biedl syndrome: BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTTC8, BBS9, BBS10, TRIM32, BBS12, CEP290, and MKS1. Inheritance is autosomal recessive. Hypothalamic hamartoma and bifid epiglottis are rare manifestations of Bardet-Biedl syndrome [Stevens & Ledbetter 2005]. Smith-Lemli-Opitz syndrome (SLOS) is a congenital multiple anomaly syndrome caused by an abnormality in cholesterol metabolism resulting from deficiency of the enzyme 7-dehydrocholesterol reductase. It is characterized by prenatal and postnatal growth retardation, microcephaly, moderate-to-severe intellectual disability, and multiple major and minor malformations including postaxial polydactyly. DHCR7 is the only gene known to be associated with SLOS. Inheritance is autosomal recessive. Hypothalamic hamartoma. Nonsyndromic or isolated hypothalamic hamartomas may cause either endocrine disturbance (most commonly, growth hormone deficiency or precocious puberty) or a severe neurologic picture of refractory seizures, behavior problems, and cognitive decline. Gelastic epilepsy may be associated. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with Pallister-Hall syndrome (PHS), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Pallister-Hall syndrome (PHS), the following evaluations are recommended:Assessment for cortisol deficiency. This must be performed urgently in individuals who have no family history of PHS and in individuals who have family members with PHS and cortisol deficiency. Of note, adrenal crisis can be lethal in infants who have not undergone proper evaluation and treatment for adrenal insufficiency. Consultation by an endocrinologist, including evaluation of growth hormone secretion, FSH and LH secretion, and serum concentration of thyroid hormone in early infancy after evaluation for and treatment of ACTH deficiency Cranial MRI to establish the location and extent of hamartoma Neurologic examination to exclude signs of intracranial hypertension, which is not typical of hypothalamic hamartomas Limb radiographs to distinguish postaxial polydactyly from central polydactyly Renal ultrasonography to evaluate for renal anomalies Visualization of the epiglottis by laryngoscopy. Urgent evaluation by an otolaryngologist for laryngotracheal cleft when signs or symptoms of aspiration are present. Elective evaluation by an otolaryngologist in asymptomatic individuals for the purpose of establishing the diagnosis or establishing the extent of anomalies. Surgical consultation for imperforate anus or anal stenosis if present Developmental assessment Medical genetics consultationTreatment of ManifestationsEndocrine abnormalities are treated as in the general population, with treatment for cortisol deficiency being the most urgent.Anal atresia or stenosis should be treated in standard fashion.Management of epiglottic abnormalities depends on the type of abnormality and extent of respiratory compromise and is the same as in the general population. Bifid epiglottis is commonly asymptomatic and most do not require treatment, unless accompanied by clear evidence of obstruction or associated with other anomalies, such as tracheal stenosis.Seizures are treated symptomatically. Seizures associated with PHS are commonly responsive to antiepileptic drugs (AEDs), whereas seizures associated with nonsyndromic hypothalamic hamartomas are more commonly refractory to AEDs. Repair of polydactyly should be undertaken on an elective basis.If developmental delays are detected, intervention and/or special education are indicated.Prevention of Secondary ComplicationsOnly under the most unusual circumstances should a hypothalamic hamartoma be removed or even biopsied because the complications of surgery and the need for lifelong hormone supplements postoperatively generally outweigh the benefits.Use of stimulants for attention deficit disorder should be considered carefully in persons with a CNS lesion that predisposes to seizures (e.g., hypothalamic hamartoma).SurveillanceDuring childhoodAnnual medical evaluations to assess growth and monitor for signs of precocious puberty Annual screening for developmental delay or learning disorders Agents/Circumstances to AvoidAs noted in Prevention of Secondary Complications, some stimulants (commonly used for attention deficit and hyperactivity disorders) may exacerbate seizures. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management Pregnancy management of a woman affected with PHS should be attuned to guidelines for the specific manifestations of the disorder. For example, the management of pregnant women with gelastic epilepsy who need to take anticonvulsants is challenging. As there are no guidelines specific to PHS, the authors recommend following general guidelines for anticonvulsants in pregnancy [Borthen & Gilhus 2012]. The management of fertility and pregnancy (which is uncommon in individuals with hypopituitarism) in individuals with hypopituitarism caused by PHS is similarly challenging and again, it is recommended that general guidelines be followed [Kübler et al 2009].Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Pallister-Hall Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDGLI37p14.1Zinc finger protein GLI3GLI3 @ LOVDGLI3Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Pallister-Hall Syndrome (View All in OMIM) View in own window 146510PALLISTER-HALL SYNDROME; PHS 165240GLI-KRUPPEL FAMILY MEMBER 3; GLI3Normal allelic variants. GLI3 extends over approximately 276 kb and includes 15 exons. The mRNA is approximately 8 kb, the reference cDNA is 8,209 bp (NM_000168.3, NP_000159.3), and the open reading frame is 4,740 bp. A number of putative normal allelic variants exist in GLI3 (Table 2; pdf). Most of the variants have been seen in multiple unrelated persons and are not believed to be associated with any phenotypic effects, although they have not been rigorously analyzed for subtle effects. They are included in Table 2 if they lie within an exon or if they are in an intron within 25 bp of an exon. Readers should refer to dbSNP to confirm these data and for additional data. (SNPs are from Human Genome build 126). Pathologic allelic variants. Selected pathologic variants reported in individuals with PHS are in Table 3 (pdf). Multiple new mutations have been identified by Johnston et al [2005]. Normal gene product. The gene encodes a protein of 1,580 amino acids. Note: As the result of a cDNA sequencing error, older citations described a longer open reading frame that predicted a protein of 1,596 amino acids; the error has been corrected in the GenBank entry NM_000168.3. Abnormal gene product. It has been shown that truncated forms of the GLI3 protein repress transcription [Shin et al 1999].