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.

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.

Myelopathy associated with Maroteaux-Lamy syndrome.

Myelopathy due to compression of the cervical spinal cord by thickened dura developed in a patient with Maroteaux-Lamy syndrome. During the last trimester of pregnancy there was severe neurological deterioration with spastic quadriparesis and impairment of sphincter function. Two months after delivery ther had been no improvement, so a cervical laminectomy and longitudinal splitting of the dura from C-5 to the foramen magnum was done. Good return of function resulted.

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.

Dyskeratosis congenita: two examples of this multisystem disorder.

Two brothers with the X-linked disorder, dyskeratosis congenita, are described. They showed the dermatologic triad of reticular hyperpigmentation, dystrophic nails, and leukoplakia oris as well as the other major feature of this disorder, aplastic anemia. Less common features observed included prenatal and postnatal growth retardation, mental retardation, elevated immunoglobulin levels, and gastrointestinal hemorrhage from mucosal ulceration. Previously unreported findings were intracranial calcifications and nutmeg-like cirrhotic changes of the liver. These brothers demonstrated that skeletal changes and bony fragility may predate anemia or steroid therapy. Although a DNA repair defect is postulated as a possible primary defect, cytogenetic studies revealed no evidence of increased chromosomal breakage.

Familial Hirschsprung's disease and type D brachydactyly: a report of four affected males in two generations.

Hirschsprung's disease usually occurs as an isolated malformation as a result of multifactorial causation. A family in which four males (two brothers and two maternal uncles) had Hirschsprung's disease and absence or hypoplasia of the nails and distal phalanges of the great toe and thumb (type D brachydactyly) is described. Hand abnormalities were not present in any other family members, and the obligate heterozygous females were without gastrointestinal problems. The pattern of inheritance was consistent with X-linked recessive inheritance; however, autosomal dominant inheritance with incomplete penetrance in females or multifactorial causation could not be completely excluded.

Teratogenicity of anticonvulsant drugs. III: Radiographic hand analysis of children exposed in utero to diphenylhydantoin.

As part of a prospective study of the teratogenicity of anticonvulsant drugs, hand radiographs were obtained on 51 children born to epileptic mothers. The phalanges and metacarpals were measured and a diagnosis of distal digital hypoplasia (DDH) was made if the distal phalangeal to other digital bone ratio was more than 2 SD below the mean for age in at least two of the digits. By these criteria, roughly 30% of infants exposed to diphenylhydantoin in utero demonstrate DDH; this was in close agreement with the clinical diagnosis of DDH. The data suggest that there is no familial tendency to the expression of this teratogenicity, there is no sex influence, there is no difference between exposure to diphenylhydantoin alone and diphenylhydantoin in combination with other anticonvulsants, and that the digital changes occur most often in the absence of other sequelae of in utero exposure to diphenylhydantoin.

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.

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.

Isolated acid neuraminidase deficiency: a distinct lysosomal storage disease.

An 8-month-old female presented with coarse facies and hepatosplenomegaly at birth. Growth proceeded at an accelerated rate and mental development was normal. A pattern of dysostosis multiplex developed radiographically. Cytoplasmic inclusions consistent with lysosomal storage disease were demonstrated by electron microscopy in bone marrow, liver, and cartilage cells and in cultured skin fibroblasts. Assays of the fibroblasts revealed a specific deficiency of acid neuraminidase and 6-fold increase in intracellular bound sialic acid. An unidentified macromolecular compound rich in sialic acid was excreted in excessive amounts in the urine. The phenotype suggests defective degradation primarily of glycoproteins and possibly to a lesser extent of keratan sulfate and gangliosides.

Brief clinical report: early recognition of the Coffin-Lowry syndrome.

We report a 2-year-old male infant with the Coffin-Lowry syndrome, and describe the change in his clinical and radiographic manifestations during the first 2 years of life. Review of published cases of the Coffin-Lowry syndrome indicates that these manifestations are progressive, and that all of the associated characteristics may not be apparent in early childhood. The importance of continued evaluations of these patients and examination of relatives for mild manifestations is emphasized.

Survival of fetuses with 45,X: an instructive case and an hypothesis.

The high (greater than 95%) fetal loss rate of 45,X embryos and fetuses has led to the suggestion that fetal survival with this karyotype requires the presence of mosaicism. However, in many instances, even given a "mild Ullrich-Turner syndrome" phenotype, mosaicism is not detected. In a pregnancy studied for advanced maternal age, CVS cultured cells showed 65% 45,X and 35% 46,X,r(X). After termination, 2 fetal tissues showed 95% 45,X cells. It is suggested that infants with the 45,X karyotype likely had mosaicism for a structurally abnormal X or Y chromosome during embryogenesis, but the abnormal cell line disappeared prior to birth.

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.

An autosomal dominant syndrome of radial hypoplasia, triphalangeal thumbs, hypospadias, and maxillary diastema.

We describe a family in which eight persons (three males, five females) in three generations had a syndrome of bilateral and strikingly symmetrical triphalangeal thumbs and radial hypoplasia. The affected males also had a first-degree hypospadias and all affected family members had an anterior maxillary diastema. The syndrome was inherited in an autosomal dominant fashion.

Teratogenicity of anticonvulsant drugs. IV: The association of clefting and epilepsy.

Cleft lip with or without cleft palate (CL/P) is the most common congenital malformation reported among infants of epileptic mothers. This study sought to examine the relative roles of anticonvulsant teratogenicity and other factors responsible for this association. Among 175 families with a proband with isolated CL/P, there were 13 parents with epilepsy and a high frequency of other family members with CL/P and epilepsy. Evaluation of the 13 cases suggested that teratogenicity of anticonvulsant drugs was not the primary factor responsible for the observed association of maternal epilepsy and clefting. Among 140 families with a proband with clefting other than CL/P, there were no instances of parental epilepsy observed.

Microcephaly and digital anomalies: a newly recognized syndrome of recessively inherited mental retardation.

We describe 2 brothers with congenital microcephaly and moderately severe mental retardation. The presence of identical and symmetrical digital anomalies suggests that this constellation represents a clinically recognizable recessively inherited mental retardation syndrome. Recognition of the clinical diagnosis should provide accurate genetic counseling to parents of a single affected child.

De novo 21q interstitial deletion in a retarded boy with ulno-fibular dysostosis.

A 9-year-old boy was referred for evaluation of multiple anomalies and mental retardation. Skeletal abnormalities had been noted at birth: joint contractures, right acetabular "dysplasia," ulno-fibular dysostosis, and bilateral talipes equinovarus with calcaneocuboid fusion. Additional findings at 9 years included short stature, unusual facial appearance, camptodactyly of several digits, undescended testes, and syndactyly of toes 4 and 5. On psychological testing he was found to be moderately retarded. Cytogenetic analysis of chromosome bands using Q, GTG, R, and C banding showed an interstitial deletion of 21q; karyotype designation: 46,XY, del (21)(pter----q11.2::q22.1----qter). Parental chromosomes were normal. Manifestations in this boy, including the joint contractures, are similar to those described in the monosomy 21 syndrome. Ulno-fibular dysostosis has not been reported previously with abnormalities of chromosome 21. To our knowledge, this is the second patient reported with an interstitial deletion of chromosome 21, and the patients are phenotypically dissimilar.

Apparent Ruvalcaba syndrome with genitourinary abnormalities.

The Ruvalcaba syndrome is a rare malformation syndrome characterized by skeletal dysplasia, facial anomalies, and mental retardation. We report on a 22-year-old woman with severe growth and mental retardation and numerous manifestations characteristic of the Ruvalcaba syndrome. In addition, she has several anomalies not previously described in the Ruvalcaba syndrome, including upslanting palpebral fissures, torus palatinus, hiatal hernia with gastroesophageal reflux, recurrent respiratory infections, pectus excavatum, equinovarous deformity, hypotonia, unilateral renal hypoplasia, an accessory ovary, and atretic fallopian tube. Review of published reports of Ruvalcaba syndrome confirms variability of the clinical and radiographic changes. Findings present in at least 50% of reported patients include mental retardation, short stature, pubertal delay, an abnormal nose (usually beaked) with hypoplastic nasal alae, microstomia with narrow maxilla, thin upper lip vermilion, broad hips, small hands, joint limitation, short fingers and toes, and vertebral abnormalities. Because 5 of the reported patients had renal abnormalities, a renal ultrasound or contrast study is indicated in the evaluation of these patients. Additional reports, particular from multiplex families, will be important to better characterize this syndrome.

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.

The Weissenbacher-Zweymüller syndrome: possible neonatal expression of the Stickler syndrome.

The Robin anomaly is a recognized presenting manifestation of the Stickler syndrome, an autosomal dominantly inherited disorder originally termed "hereditary progressive arthroophthalmopathy." We report an infant with the Robin anomaly, myopia and dumbbell-shaped femora and humeri in a family with the Stickler syndrome. This observation suggests that the Weissenbacher-Zweymüller syndrome is in fact a variant of the Stickler syndrome.