Thaddeus E. Kelly

The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3

IPEX is a fatal disorder characterized by immune dysregulation, polyendocrinopathy, enteropathy and X-linked inheritance (MIM 304930). We present genetic evidence that different mutations of the human gene FOXP3, the ortholog of the gene mutated in scurfy mice (Foxp3), causes IPEX syndrome. Recent linkage analysis studies mapped the gene mutated in IPEX to an interval of 17–20-cM at Xp11.23–Xq13.3 (refs. 1,2).

Evidence for digenic inheritance in some cases of Antley-Bixler syndrome?

The Antley-Bixler syndrome has been thought to be caused by an autosomal recessive gene. However, patients with this phenotype have been reported with a new dominant mutation at theFGFR2 locus as well as in the offspring of mothers taking the antifungal agent fluconazole during early pregnancy. In addition to the craniosynostosis and joint ankylosis which are the clinical hallmarks of the condition, many patients, especially females, have genital abnormalities. We now report abnormalities of steroid biogenesis in seven of 16 patients with an Antley-Bixler phenotype. Additionally, we identify FGFR2 mutations in seven of these 16 patients, including one patient with abnormal steroidogenesis. These findings, suggesting that some cases of Antley-Bixler syndrome are the outcome of two distinct genetic events, allow a hypothesis to be formulated under which we may explain all the differing and seemingly contradictory circumstances in which the Antley-Bixler phenotype has been recognised.

Manifestations and linkage analysis in X‐linked autoimmunity‐immunodeficiency syndrome

The clinical findings of a kindred with an X-linked disorder are characterized by autoimmune polyendocrinopathy, enteropathy with villous atrophy, chronic dermatitis, and variable immunodeficiency. Linkage analysis was performed on 20 members of the affected kindred to determine the location of the responsible locus. Informative recombinations limited the region to an approximate 20 cM interval bordered by DXS1055 and DXS1196/DXS1050. Multipoint analysis generated a lod score >3 for the region contained between DXS8024 and DXS8031. The candidate region includes the Wiskott-Aldrich syndrome (WAS) locus. Evaluation of the Wiskott-Aldrich syndrome protein gene by single strand conformational analysis, heteroduplex analysis, and direct sequencing of the 12 exons in an affected male and two carrier females revealed no abnormalities. We conclude that this kindred has an X-linked disorder, distinct from WAS, that results in autoimmunity and variable immunodeficiency. The responsible locus maps to the pericentromeric region Xp11.23 to Xq21.1.

Constitutional UPD for chromosome 11p15 in individuals with isolated hemihyperplasia is associated with high tumor risk and occurs following assisted reproductive technologies

Isolated hemihyperplasia (IH) refers to a distinct diagnosis involving asymmetric overgrowth of single or multiple organs or regions of the body and can result from various genomic changes including molecular alterations of 11p15; these are paternal uniparental disomy (UPD), and alterations of methylation at two imprinting centers at 11p15: IC1 (H19) and IC2 (KCNQ1OT1). As little information is available on the molecular basis of tumor development in IH, or on the frequency of tumors in children with different molecular subtypes of IH, molecular testing was undertaken on 51 patients with IH and revealed: 8 (16%) with UPD, 3 (6%) with hypomethylation at KCNQ1OT1, and 0 with hypermethylation at H19. Of the 8 patients with UPD, 4 had tumors (3 hepatoblastomas, 1 Wilms tumor); 0/3 patients with hypomethylation at KCNQ1OT1 had a tumor; of the remaining 40 with no molecular alterations, 6 had tumors (3 Wilms tumors, 2 neuroblastomas, 1 adrenocortical adenoma). The 50% tumor frequency in patients with IH and UPD was statistically significantly higher than the 15% tumor frequency in those with IH and no molecular alteration detected (Fishers exact test P = 0.047, OR 5.67). This is the first demonstration that UPD at 11p15 in patients with IH confers a higher tumor risk than in patients with IH without this molecular change. Of note, two of the eight patients with UPD and IH were conceived using assisted reproductive technologies (ART), thus raising the question whether ART might impact the rate of somatic recombination during embryonic development.

Observations Suggesting Allelism of the Achondroplasia and Hypochondroplasia Genes

It is argued that there are at least two alleles at the achondroplasia locus: one responsible for classic achondroplasia and one responsible for hypochondroplasia. Homozygosity for the achondroplasia gene produces a lethal skeletal dysplasia; homozygosity for hypochondroplasia has not been described. We report here a child considered to be a genetic compound for the achondroplasia and hypochondroplasia alleles.

Multiple areas of intestinal atresia associated with immunodeficiency and posttransfusion graft-versus-host disease

We describe an infant with multiple segmental areas of atresia of the small and large bowel, with histologic features characteristic of the hereditary form of the disease. Posttransfusion graft-versus-host disease developed first, and then immunodeficiency was found. This report confirms the association between hereditary multiple intestinal atresia and immunodeficiency. We recommend irradiation of blood products in patients with multiple intestinal atresia pending evaluation of immune system status.

Autosomal recessive congenital cerebellar hypoplasia.

We report three sibling pairs with congenital cerebellar hypoplasia. All six children presented in the first years of life with delays in motor and language development. All patients showed cerebellar and/or vermal dysfunction and, on formal psychometric testing, cognitive abilities ranged from normal to moderately retarded. Abnormalities on CT scan ranged from prominent valleculla to an enlarged cisterna magna with hypoplasia of the cerebellar hemispheres and vermis. The pedigrees are consistent with autosomal recessive inheritance.

Hereditary motor-sensory neuropathy(HMSN): Possible X-linked dominant inheritance

The inheritance of the hereditary motor and sensory neuropathies (HMSN) is usually autosomal dominant. We studied a kinship with a pattern of X-linked dominant inheritance. The phenotype was similar to HMSN of the “intermediate” type. Men were more severely affected than women, and hypertrophic nerves were not found. Nerve conduction was very slow in men, but it was mildly slow or normal in women. No male-to-male transmission was found in six generations.

Discordant phenotypes and 45,X/46,X,idic(Y).

Mosaicism introduces wide variability into the clinical expression of numerical and unbalanced structural chromosomal abnormalities. The phenotypic range of variability of 45,X/46,XY mosaicism extends from Turner syndrome to mixed gonadal dysgenesis to normal males. The specific phenotype is primarily dependent on the chromosomal constitution of the developing gonad. Similar phenotypic variability is observed with mosaicism for 45,X and a second cell line with an abnormal sex chromosome. This report describes a patient with Turner syndrome and a patient with mixed gonadal dysgenesis who have identical karyotypes, namely 45,X/46,X,idic(Y)(p11.2). While mosaicism alone might have accounted for the phenotypic differences, by PCR analysis the Turner syndrome patient was SRY and ZFY negative and the mixed gonadal dysgenesis patient was SRY and ZFY positive.

Ganglioside GM2 N-acetyl-ß-D-gafactosaminidase and asialo GM2 (GA2) N-acetyl-ß-D-galactosaminidase; studies in human skin fibroblasts

Ganglioside GM2 and its asialo‐derivative, GA2 were radiolabeled in their N‐acetyl‐D‐galactosaminyl moieties by oxidation with galactose oxidase and reduction with tritiated sodium borohydride. Specific activities of 6 × 104 dpm/nmol (GM2) and 1.8 × 106 dpm/nmol (GA2) were achieved. About 98% of the label was in N‐acetyl‐D‐galactosamine. Using these substrates, an assay was developed for GM2‐N‐acetyl‐β‐D‐galactosaminidase (E.C.3.2.1.30) and GA2‐N‐acetyl‐β‐D‐galactosaminidase (E.C.3.2.1.30) activities in human cultured skin fibroblasts. The products of the GM2 cleaving reaction were identified as N‐acetylgalactosamine and ganglioside GM3‐ Both GM2 and GA2 cleaving activities were stimulated about 5‐fold by purified sodium taurocholate, and this stimulation was inhibited by neutral detergents, lipids and albumin at low concentrations. Addition of various salts, reducing agents and a protein activator factor from human liver of Li et al. (1973) did not stimulate GM2‐N‐acetyl‐β‐D‐galactosaminidase activity beyond that found with sodium taurocholate. Under optimal conditions, control fibroblast supernates cleaved ganglioside GM2 at a rate of 3.7 nmol/mg protein/h compared to 1100 for GA2‐N‐acetyl‐β‐D‐galactosaminidase and 4700 for 4‐methylumbelliferyl‐N‐acetyl‐β‐D‐glucosaminidase. Supernates from two patients with Tay‐Sachs disease had markedly reduced activity levels for GM2‐N‐acetyl‐β‐D‐galactosaminidase but not for the other two substrates. Supernates from two patients with Sandhoffs disease had reduced activities for all three substrates. A supernate from one patient with juvenile GM2 gangliosidosis cleaved GM2 at a somewhat faster rate than those from Tay‐Sachs or Sandhoffs patients. Two healthy adult women with markedly reduced hexosaminidase A activities using 4MU‐N‐acetyl‐β‐D‐glucosaminide as substrate had approximately half‐normal activities using GM2 as substrate. A patient with the Tay‐Sachs phenotype but with a partial deficiency of hexosaminidase A using the 4‐MU substrate had a profound deficiency using GM2 as substrate. In such unusual hexosaminidase mutants, assays using GM2 as substrate are better indicators of phenotype than those using synthetic substrates.