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. Am. J. Med. Genet. 94:64–67, 2000. Published 2000 Wiley‐Liss, Inc.     

A patient with a ring chromosome 2 and microdeletion of 2q detected using FISH: Further support for "ring chromosome 2 syndrome"

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.     

New insights into genotype–phenotype correlation for GLI3 mutations

The phenotypic spectrum of GLI3 mutations includes autosomal dominant Greig cephalopolysyndactyly syndrome (GCPS) and Pallister–Hall syndrome (PHS). PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis. Typical GCPS combines polysyndactyly of hands and feet and craniofacial features. Genotype–phenotype correlations have been found both for the location and the nature of GLI3 mutations, highlighting the bifunctional nature of GLI3 during development. Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases). Most of mutations are novel and consistent with the previously reported genotype–phenotype correlation. Our results also show a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS. Fetal PHS observations emphasize on the possible lethality of GLI3 mutations and extend the phenotypic spectrum of malformations such as agnathia and reductional limbs defects. GLI3 expression studied by in situ hybridization during human development confirms its early expression in target tissues.     

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.     

Stringent delineation of Pallister-Hall syndrome in two long surviving patients: importance of radiological anomalies of the hands.

We report two unrelated, long surviving patients (2 and 17 years) with syndromal 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. In the oldest patient, the hamartoma caused precocious puberty of the central type, combined with complete hGH deficiency. Both patients showed bony anomalies of the extremities: variable proximal synostosis between central (2nd to 4th) metacarpals or intercalary polydactyly with generalised brachydactyly, severe brachytelephalangism, syndactyly, and nail hypoplasia. Together with the absence of anomalies of cholesterol metabolism, a combination of oral frenula, laryngeal malformations, digestive abnormalities, intercalary polysyndactyly, generalised brachytelephalangism, and nail hypoplasia should allow the delineation of Pallister-Hall syndrome, even when a CNS tumour is absent. The radiological abnormalities are helpful in differentiating Pallister-Hall syndrome from the other syndromes in which hypothalamic hamartoblastoma is observed. This is of major importance for genetic counselling, since Pallister-Hall syndrome may be a dominantly inherited disorder, thus contrasting with most of the other disorders with the CAVE phenotype, which are recessively inherited.     

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.     

Oral-facial-digital syndrome with Y-shaped fourth metacarpals and endocardial cushion defect.

We report on a boy with pseudo-cleft of the upper lip, cleft palate, bifid uvula, lobulated tongue, hypoplasia of the epiglottis, both preaxial and central polydactyly of the hands (Y-shaped fourth metacarpals), bilateral preaxial polydactyly of the feet, postaxial polydactyly of the left foot, hearing impairment, and congenital heart disease with endocardial cushion defect. These clinical manifestations resembled oral-facial-digital syndrome type II (OFDS II, Mohr syndrome) or type VI (Váradi syndrome), associated with an atrioventricular canal. Clinical variability of OFDS II has been observed repeatedly. To the best of our knowledge, this is the first reported case of OFDS II with Y-shaped fourth metacarpals. In addition to Y-shaped fourth metacarpals, Mohr syndrome plus atrioventricular canal and hypoplasia of the epiglottis may represent an additional subgroup of OFDS.     

Bifid tongue: a rare feature associated with infants of diabetic mother syndrome

Infants born to diabetic mothers (IDM) are well documented to have a higher rate of congenital malformations. Sacral agenesis/hypogenesis and caudal dysgenesis are classically linked to maternal diabetes, but many other types of anomalies are more frequent. In this case report, we describe a male infant born to a diabetic mother who in addition to other typical congenital abnormalities was born with an impressive bifid tongue. Accompanying congenital anomalies include unilateral microphthalmia, bilateral microtia, cleft palate, micropenis with unilateral cryptorchidism, bilateral radial hypoplasia, unilateral pre-axial polydactyly, and mid-line central nervous system defects including arhinencephaly and pituitary hypoplasia. Review of the literature reveals an additional case of an infant with a bifid tongue born to a diabetic mother [Comess et al., 1969]. In conclusion, bifid tongue without oral hamartoma, a rare congenital anomaly, can be an associated finding in IDM.     

Oral-facial-digital syndrome with Y-shaped fourth metacarpals and endocardial cushion defect

We report on a boy with pseudo-cleft of the upper lip, cleft palate, bifid uvula, lobulated tongue, hypoplasia of the epiglottis, both preaxial and central polydactyly of the hands (Y-shaped fourth metacarpals), bilateral preaxial polydactyly of the feet, postaxial polydactyly of the left foot, hearing impairment, and congenital heart disease with endocardial cushion defect. These clinical manifestations resembled oral-facial-digital syndrome type II (OFDS II, Mohr syndrome) or type VI (Váradi syndrome), associated with an atrioventricular canal. Clinical variability of OFDS II has been observed repeatedly. To the best of our knowledge, this is the first reported case of OFDS II with Y-shaped fourth metacarpals. In addition to Y-shaped fourth metacarpals, Mohr syndrome plus atrioventricular canal and hypoplasia of the epiglottis may represent an additional subgroup of OFDS. Am. J. Med. Genet. 86: 278–281, 1999. © 1999 Wiley-Liss, Inc.     

Exclusion of candidate loci and cholesterol biosynthetic abnormalities in familial Pallister-Hall syndrome.

Pallister-Hall syndrome (PHS) was originally described in 1980 in six sporadic cases of children with structural anomalies including hypothalamic hamartoma, polydactyly, imperforate anus, and renal and pulmonary anomalies. In 1993, the first familial cases were reported, including affected sibs and vertical transmission. Three of these families are sufficiently large to allow initial evaluation by linkage studies to candidate genes or loci. We have evaluated candidate loci for PHS based on three clinical observations. The first is a patient with PHS-like malformations, including a hypothalamic hamartoma, and an unbalanced translocation involving 7q and 3p. The second is a family with familial PHS where the founder's father had an autosomal dominant hand malformation previously mapped to 17q. The third is the phenotypic overlap of PHS and Smith-Lemli-Opitz syndrome. In this report, we exclude these loci as candidates for linkage to the PHS phenotype on the basis of lod scores of less than-2.0. We conclude that hypothalamic hamartoma is not specific to PHS and that the dominant hand malformation in one of the families was a coincidence. To evaluate the relationship of PHS to Smith-Lemli-Opitz syndrome, we analysed levels of cholesterol and intermediate metabolites of the later stages of cholesterol biosynthesis. There is no evidence of a generalised disorder of cholesterol biosynthesis in patients with familial PHS. On genetic and biochemical grounds, we conclude that PHS and Smith-Lemli-Opitz syndrome are not allelic variants of a single locus.     

Steinfeld syndrome: Report of a second family and further delineation of a rare autosomal dominant disorder

We report on a fetus with alobar holoprosencephaly, microphthalmia, midline cleft lip and palate, absent nose, dysplastic ears, radial defects, pentalogy of Fallot, unilateral renal aplasia, absent gallbladder, vertebral anomalies, and absence of ribs. The father had a cleft palate, bilateral colobomas of the iris and retina, a bifid uvula, vertebral anomalies, and unilateral congential hearing loss. His sister had a cleft lip. On the basis of this family and the family reported by Steinfeld [1982], this malformation syndrome can be defined as a rare autosomal dominant syndrome whose main component manifestations are holoprosencephaly, predominantly radial limb deficiency, heart defects, kidney malformations, absence of gallbladder, and vertebral anomalies. © 1993 Wiley-Liss, Inc.     

Orofaciodigital syndrome type IV (Mohr-Majewski syndrome) with severe expression expanding the known spectrum of anomalies.

We present a male infant with hypertelorism, median pseudo-cleft of the upper lip and cleft palate, lobulated tongue, hypoplastic larynx and epiglottis, mesomelic shortening of limbs with particularly short and broad tibiae, polydactyly of the upper limbs, severely hypoplastic external genitalia with anorchidism, anal atresia, severe congenital heart defect, and renal agenesis. These features show considerable overlap with severe Majewski type short rib-polydactyly syndrome and so expand the known spectrum of anomalies in orofaciodigital syndrome type IV.     

The Richieri-Costa and Pereira syndrome: report of two Brazilian siblings and review of literature

Richieri-Costa and Pereira syndrome is a rare autosomal recessive disorder characterized specially by Pierre Robin sequence with cleft mandible and limb anomalies. There are a typical laryngeal anomaly which encompass short and round larynx, absent or abnormal epiglottis, and abnormal aryepiglottic folds. Most patients reported were from Brazil. We describe a brother and sister with Richieri-Costa and Pereira syndrome on another Brazilian family documenting their physical findings and laryngeal defects. We also review the literature and discuss the main clinical characteristics and etiology.     

Congenital hypothyroidism, spiky hair, and cleft palate.

Two brothers are described with athyroidal hypothyroidism, spiky hair, choanal atresia, cleft palate, and bifid epiglottis. Polyhydramnios was present in the third trimester of each pregnancy. These abnormalities appear to represent a new syndrome.     

A novel ZRS mutation in a Balochi tribal family with triphalangeal thumb, pre-axial polydactyly, post-axial polydactyly, and syndactyly

Limb malformations are one of the most common types of human congenital malformations. Mutations in the ZRS enhancer of Sonic Hedgehog are thought to be responsible for pre-axial polydactyly in multiple independent families. Here, we describe a large Balochi tribal family from Southern Punjab, Pakistan, with a variable set of limb malformations and a novel ZRS mutation. The family has a limb phenotype characterized by triphalangeal thumb, pre-axial polydactyly, and post-axial polydactyly. There is also a high degree of phenotypic heterogeneity with less common clinical findings in the affected family members that include osseous syndactyly of forth-fifth fingers, clinodactyly, hypoplasia of mesoaxial fingers, and bifid halluces. The presentation in most of the affected patients was bilateral and symmetrical. A heterozygous C>A mutation at position 287 of the ZRS enhancer (chr7:156,584,283; hg19) was detected in all affected subjects and is absent from four unaffected family members, 42 unrelated samples, and multiple databases of human variation. Combined, these results identify a novel ZRS287 C>A mutation which leads to a variable spectrum of limb phenotypes.     

Ellis-van Creveld syndrome: report of 15 cases in an inbred kindred.

An inbred kindred with 15 cases of the autosomal recessive Ellis-van Creveld syndrome is reported. The ages of the 12 living affected varied between 3 and 82 years. The main characteristics include polydactyly of the hands and feet and several other skeletal anomalies, oral manifestations, and malformations of the heart in 50% of the living affected.