Margaret H. Abbott

Report from the workshop on Pallister-Hall syndrome and related phenotypes

A one day workshop was convened on the NIH campus on March 1, 1996, in Bethesda, Maryland to discuss emerging clinical and molecular information on Pallister-Hall syndrome (PHS) and related disorders. PHS is a pleiotropic autosomal dominant disorder comprising hypothalamic hamartoma, pituitary dysfunction, central polydactyly, and visceral malformations. The goals of the meeting were to update participants in the latest clinical and research findings in the disorder, review the history and evolution of the understanding of the phenotype, determine diagnostic criteria for PHS, and make recommendations for clinical evaluation of individuals affected by PHS. These topics were addressed by several speakers and data were displayed from several of the large pedigrees of autosomal dominant PHS. 37 refs., 4 tabs.

Linkage mapping and phenotypic analysis of autosomal dominant Pallister-Hall syndrome

Pallister-Hall syndrome is a human developmental disorder that is inherited in an autosomal dominant pattern. The phenotypic features of the syndrome include hypothalamic hamartoma, polydactyly, imperforate anus, laryngeal clefting, and other anomalies. Here we describe the clinical characterisation of a family with 22 affected members and the genetic mapping of the corresponding locus. Clinical, radiographic, and endoscopic evaluations showed that this disorder is a fully penetrant trait with variable expressivity and low morbidity. By analysing 60 subjects in two families using anonymous STRP markers, we have established linkage to 7p13 by two point analysis with D7S691 resulting in a lod score of 7.0 at theta = 0, near the GLI3 locus. Deletions and translocations in GLI3 are associated with the Greig cephalopolysyndactyly syndrome. Although Greig cephalopolysyndactyly syndrome has some phenotypic overlap with Pallister-Hall syndrome, these two disorders are clinically distinct. The colocalisation of loci for these distinct phenotypes led us to analyse GLI3 for mutations in patients with Pallister-Hall syndrome. We have previously shown GLI3 mutations in two other small, moderately affected families with Pallister-Hall syndrome. The linkage data reported here suggest that these larger, mildly affected families may also have mutations in GLI3.

Kinetics and Distribution of 111Indium-Labeled Platelets in Patients with Homocystinuria

Homocystinuria is an inborn error of metabolism involving a high incidence of thromboembolism. It sometimes improves with large doses of pyridoxine. We investigated the kinetics and distribution of 111Indoxine-labeled platelets in 11 normal volunteers and 12 patients with homocystinuria, none of whom had clinical evidence of acute thrombosis at the time of the study. Six of the patients were resistant to pyridoxine and had homocystinemia. There were no statistical differences in mean platelet-survival times between pyridoxine responders and nonresponders or between normal subjects and pyridoxine responders or nonresponders, regardless of whether a linear, exponential, or multiple-hit model was used to analyze the kinetic data. Plasma homocystine levels had no apparent effect on mean platelet-survival time. There was no abnormal accumulation of platelets in any of the patients, and the distribution of platelets in liver and spleen was similar to that in normal subjects. Our results suggest that the kinetics and distribution of platelets in patients with homocystinuria who have no clinical evidence of thromboembolism are normal. Thus, the data do not provide evidence for disordered platelet function or for an ongoing interaction of platelets with vessel walls in this condition.

Overlap of PIV syndrome, VACTERL and Pallister–Hall syndrome: clinical and molecular analysis

The polydactyly, imperforate anus, vertebral anomalies syndrome (PIV, OMIM 174100) was determined as a distinct syndrome by Say and Gerald in 1968 (Say B, Gerald PS. Lancet 1968: 2: 688). We noted that the features of PIV overlap with the VATER association and Pallister–Hall syndrome (PHS, OMIM 146510), which includes polydactyly, (central or postaxial), shortened fingers, hypoplastic nails, renal anomalies, imperforate anus, and hypothalamic hamartoma. Truncation mutations in GLI3, a zinc finger transcription factor gene, have been shown to cause PHS. We performed a molecular evaluation on a patient diagnosed with PIV, whose mother, grandfather, and maternal aunt had similar malformations. We sequenced the GLI3 gene in the patient to determine if she had a mutation. The patient was found to have a deletion in nucleotides 2188–2207 causing a frameshift mutation that predicts a truncated protein product of the gene. Later clinical studies demonstrated that the patient also has a hypothalamic hamartoma, a finding in PHS. We concluded that this family had atypical PHS and not PIV. This result has prompted us to re‐evaluate the PIV literature to see if PIV is a valid entity. Based on these data and our examination of the literature, we conclude that PIV is not a valid diagnostic entity. We conclude that patients diagnosed with PIV should be reclassified as having VACTERL, or PHS, or another syndrome with overlapping malformations.

Phenotypic Heterogeneity in Huntington Disease

Two Huntington disease (HD) pedigrees are presented which differ according to mean and distribution of the age at onset, the effect of paternal transmission on the age at onset, presence of manic-depressive symptoms, and type of presenting symptoms. Together with previous reports, the data suggest clinical heterogeneity between HD kindreds which may imply some kind of genetic heterogeneity, most likely subsequent mutation at a single HD locus. The possibility of genetic heterogeneity has important consequences, both in research, and in the counseling and care of families and patients with differing manifestations of the disease.

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 founders 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.

Concentration of mutations causing Schmid metaphyseal chondrodysplasia in the NC1 domain of type X collagen

Schmid metaphyseal chondrodysplasia (SMCD, MIM 156500) is an autosomal dominant disorder of the osseous skeleton resulting in short stature, coxa vara and a waddling gait. Type X collagen is an extracellular matrix protein expressed exclusively by hypertrophic chondrocytes. We have previously identified four mutations in the type X collagen gene (COL10A1) in patients with SMCD. Each of these mutations, as well as another three reported by other investigators, are in the carboxy-terminal non-collagenous domain (NC1). Here, we present data for another three mutations each predicted to cause premature termination of translation within the NC1 domain. Two are nonsense mutations, Y628X and W651X, while the third is a frameshift resulting from the deletion of two nucleotides, 1856delCC. Each of these mutations occurred de novo, resulting in sporadic cases of SMCD. Four frameshift mutations have now been reported to initiate within 10bp of each other in the NC1 domain, namely 1865delC, 1856delCC, 1856del13 and 1866del10. These findings further support the hypothesis that SMCD is the result of the mutant type X collagen molecule being unable to participate in trimerization, although a dominant-negative model of disease pathogenesis has not been formally excluded.