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.

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.

Cervical spine anomalies and tumors in Weaver syndrome.

Weaver syndrome is an autosomal dominant disorder comprising accelerated growth rate and rapidly advancing skeletal maturation. Previous reports suggest that the phenotype in adults may be sufficiently subtle to make diagnosis difficult. Half brothers with classical childhood findings of Weaver syndrome and their father with minimal clinical findings showed cervical spine anomalies that likely represent a consistent radiographic finding in this disorder. One of the children represents the third occurrence of neoplasia in Weaver syndrome.

Spinal muscular atrophy variant with congenital fractures.

A single report of brothers born to first-cousin parents with a form of acute spinal muscular atrophy (SMA) and congenital fractures suggested that this combination represented a distinct form of autosomal recessive SMA. We describe a boy with hypotonia and congenital fractures whose sural nerve and muscle biopsies were consistent with a form of spinal muscular atrophy. Molecular studies identified no abnormality of the SMN(T) gene on chromosome 5. This case serves to validate the suggestion of a distinct and rare form of spinal muscular atrophy while not excluding possible X-linked inheritance.

Chondrodysplasia punctata stemming from maternal lupus erythematosus.

The finding of stippled epiphyses on a neonatal radiograph generates a wide differential diagnosis, including genetic and teratogenic causes. We report the case of a male infant with stippled epiphyses evident on neonatal radiographs in whom a typical rash of lupus erythematosus developed. The skin abnormalities in the infant resulted in a diagnosis of systemic lupus erythematosus in his mother. Over a 3-year follow-up period, the child has demonstrated strikingly short stature, midface hypoplasia, anomalous digital development, slow resolution of the stippled epiphyses, and near normal cognitive development. The differential diagnosis of chondrodysplasia punctata and the literature supporting maternal lupus as one cause are reviewed.

Extension of phenotype associated with structural mutations in type I collagen: siblings with juvenile osteoporosis have an alpha2(I)Gly436 --> Arg substitution.

Mutations in the type I collagen genes have been identified as the cause of all four types of osteogenesis imperfecta (OI). We now report a mutation that extends the phenotype associated with structural abnormalities in type I collagen. Two siblings presented with a history of back pain and were diagnosed with juvenile osteoporosis, based on clinical and radiological examination. Radiographs showed decreased lumbar bone density and multiple compression fractures throughout the thoracic and lumbar spines of both patients. One child has moderate short stature and mild neurosensory hearing loss. However, neither child has incurred the long bone fractures characteristic of OI. Protein studies demonstrated electrophoretically abnormal type I collagen in samples from both children. Enzymatic cleavage of RNA:RNA hybrids identified a mismatch in type I collagen alpha2 (COL1A2) mRNA. DNA sequencing of COL1A2 cDNA subclones defined the mismatch as a single-base mutation (1715G --> A) in both children. This mutation predicts the substitution of arginine for glycine at position 436 (G436R) in the helical domain of the alpha2(I) chain. Analysis of genomic DNA identified the mutation in the asymptomatic father, who is presumably a germ-line mosaic carrier. The presence of the same heterozygous mutation in two siblings strongly suggests that the probands display the full phenotype. Taken together, the clinical, biochemical, and molecular findings of this study extend the phenotype associated with type I collagen mutations to cases with only spine manifestations and variable short stature into adolescence.

Confined placental mosaicism for trisomy 8 and intra-uterine growth retardation.

This report describes a case of apparent confined placental mosaicism for trisomy 8 in a pregnancy which produced a male infant with intra-uterine growth retardation. Postnatal cytogenetic and molecular studies were consistent with biparental disomy 8. Postnatally, the infant experienced a period of rapid catch-up growth and exhibited no clinical features of trisomy 8 mosaicism. His development was age appropriate.

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.

Discordant puberty in monozygotic twin sisters with neurofibromatosis type 1 (NF1).

Monozygotic twin sisters are reported who have discordant pubertal growth and sexual development. Although both sisters were physiologically appropriate for chronological age in their pubertal development, their adolescent development was considerably different from that expected of monozygotic twin sisters. The more pubertally advanced sister by magnetic resonance imaging had an optic pathway glioma while none was present in her twin sister. Precocious puberty is not an unexpected complication of neurofibromatosis type 1 and is always associated with the presence of an optic pathway glioma. These sisters emphasize the striking similarity that is expected of monozygotic twins and the need for investigation when intertwin differences in growth and/or development arise.

X-linked Charcot-Marie-Tooth disease: molecular analysis of interfamilial variability.

This report describes two families with type 1 Charcot-Marie-Tooth disease (CMTX), or hereditary motor sensory neuropathy type 1. Pedigree analysis is consistent with X-linked recessive inheritance in one family and X-linked dominant inheritance in the second. In the first family, a mutation in the connexin32 gene has been demonstrated and analyzed in family members. In the second family, linkage analysis is consistent with a mutation at the same locus. This report demonstrates the interfamilial variability in X-linked CMT and underscores the observation that regardless of the pattern of inheritance, X-linked CMT constitutes a single, variable disorder.

Chondrodysplasia punctata, humero-metacarpal type: a second case.

We report on a boy with symmetrical rhizomelic shortness of the upper limbs and punctate epiphyseal calcifications noted at birth. Radiographs documented short and wide humeri, symmetrical brachymetacarpy, coronal clefts of the veretebrae, and punctate calcifications in the spine, sacrum, shoulder, feet, and trachea. Borochowitz [1991] described a similar patient with an apparently new syndrome of chondrodysplasia punctata (CP), distinct from previously described forms. He suggested the term "chondrodysplasia punctata, humero-metacarpal (HM)" type. We present our patient as a second case of this form of CP.

Molecular analysis of recombination in a family with Duchenne muscular dystrophy and a large pericentric X chromosome inversion.

It has been demonstrated in animal studies that, in animals heterozygous for pericentric chromosomal inversions, loop formation is greatly reduced during meiosis. This results in absence of recombination within the inverted segment, with recombination seen only outside the inversion. A recent study in yeast has shown that telomeres, rather than centromeres, lead in chromosome movement just prior to meiosis and may be involved in promoting recombination. We studied by cytogenetic analysis and DNA polymorphisms the nature of meiotic recombination in a three-generation family with a large pericentric X chromosome inversion, inv(X)(p21.1q26), in which Duchenne muscular dystrophy (DMD) was cosegregating with the inversion. On DNA analysis there was no evidence of meiotic recombination between the inverted and normal X chromosomes in the inverted segment. Recombination was seen at the telomeric regions, Xp22 and Xq27-28. No deletion or point mutation was found on analysis of the DMD gene. On the basis of the FISH results, we believe that the X inversion is the mutation responsible for DMD in this family. Our results indicate that (1) pericentric X chromosome inversions result in reduction of recombination between the normal and inverted X chromosomes; (2) meiotic X chromosome pairing in these individuals is likely initiated at the telomeres; and (3) in this family DMD is caused by the pericentric inversion.

Neuroectodermal (CHIME) syndrome: an additional case with long term follow up of all reported cases.

A new neuroectodermal syndrome (designated CHIME syndrome) was described in 1983 with a total of four patients reported, it is presumed to be an autosomal recessive disorder because of recurrence in sibs. The main features include ocular colobomas, congenital heart disease, early onset migratory ichthyosiform dermatosis, mental retardation, conductive hearing loss, seizures, and typical facial features. We report a fifth child with the condition, confirming the unique nature of the condition. Long term follow up information on this patient, as well as the previously described cases, provides information regarding the outcome for these patients, which includes general good health, severe mental retardation, seizures that worsen after puberty, conductive hearing loss, and chronic migratory ichthyosiform skin rash without scarring.