Genomic sequence of the DAX1 gene: an orphan nuclear receptor responsible for X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism.

The gene responsible for X-linked adrenal hypoplasia congenita, DAX1, encodes a member of the nuclear hormone receptor superfamily. We sequenced 8851 bp that contained the DAX1 genomic region. The DAX gene was composed of two exons and one 3.4-kilobase intron. Putative TATA and GC boxes and a putative steroidogenic factor 1 response element were present in the 5'-flanking region. Two potentially polymorphic short tandem repeats were identified. The first exon encoded two putative novel zinc finger motifs within a putative DNA binding domain and part of the ligand binding domain, and the second exon encoded the remainder of the ligand binding domain. Although the putative DNA binding domain of DAX1 does not contain substantial sequence similarity to other nuclear hormone receptor superfamily members, the putative ligand binding domain had remarkable similarity to other family members. Single-strand conformational polymorphism analysis permitted identification of three new mutations in DAX1. In conclusion, single-strand conformational polymorphism analysis facilitates identification of mutations in the DAX1 gene, and the short tandem repeats may permit linkage analysis in families in which mutations are not yet identified. We speculate that DAX1 may be the most primitive member of the nuclear hormone receptor superfamily identified in mammals.

The 8993 mtDNA mutation: heteroplasmy and clinical presentation in three families.

The point mutation at bp 8993 of human mtDNA in the ATPase 6 gene is associated with neurogenic weakness, ataxia and retinitis pigmentosa, and with subacute necrotizing encephalomyelopathy (Leigh disease) when present at high copy number. In this study we describe three new multiplex families with the ATPase 8993 mtDNA mutation and demonstrate a correlation between the percentage heteroplasmy of this mutation and the clinical phenotype. By combining this study with previous data we produce a graph of age of onset of symptoms versus percentage heteroplasmy of the mutation. Finally, we determine that ATP synthesis with NAD-linked substrates in cultured lymphoblast mitochondria from three patients with Leigh disease who had a high percentage heteroplasmy was on average 66% of the rate seen in control lymphoblast mitochondria. Similar rates are observed in lymphoblast mitochondria isolated from patients with Leigh disease due to complex I deficiency. This percentage appears to be independent of the rate of electron transport in mitochondria from patient cell lines with the mtDNA 8993 mutation.

Causal heterogeneity in isolated lissencephaly.

We report clinical, cytogenetic, and molecular studies in 65 patients with isolated lissencephaly sequence (ILS). All had type I lissencephaly of varying severity and a grossly normal cerebellum. Some had additional brain abnormalities. Facial appearance was essentially normal. All had severe to profound mental retardation, seizures, hypotonia that evolved into spasticity, and feeding difficulties. Clinical and laboratory studies demonstrated etiologic heterogeneity. Molecular studies detected microdeletions in chromosome band 17p13.3 in six of 44 patients tested, confirming that deletion of all or part of this "critical region" is the cause of ILS in some cases. There were slightly larger deletions in the same region in a majority of patients with Miller-Dieker syndrome. One patient had an apparently balanced, de novo reciprocal translocation with breakpoints at Xq22 and 2p25. Four sibs from two families had a new, autosomal recessive syndrome of ILS with neonatal death. Other causes supported by clinical observations include autosomal recessive inheritance, intrauterine infection, and intrauterine perfusion failure. Those ILS probands in whom no etiology could be established had 41 sibs of whom three were affected, giving an empiric recurrence risk of 7%.

Williams syndrome: features in late childhood and adolescence.

Nine children with the Williams syndrome were evaluated for physical, neurodevelopmental, and behavioral characteristics to record the natural history of this disorder. The study subjects, who ranged in age from 10 years to 20 years, generally showed lower than expected cognitive functioning with four of the nine functioning in the severely retarded range. However, all the children showed uneven developmental profiles, compared to measured IQ, with reading abilities exceeding the expected level and visual-motor skills deficient for overall performance expectations. All but one child had evidence of supravalvular aortic stenosis on echocardiography, but there was little morbidity from cardiovascular disease in this group of patients. Although all had grown at or below the fifth percentile in early childhood, seven now were above the fifth percentile for height. Personality attributes that characterize younger children with Williams syndrome persisted in this group of older children.

Clinical-ultrastructural study of a retinal dystrophy.

An ultrastructural and cytochemical study was performed on the retina and retinal pigment epithelium of an eye surgically enucleated for choroidal melanoma from an otherwise healthy 31-year-old man. The patient and his identical twin show a retinal dystrophy that, based on clinical appearance, visual fields, amd electrophysiology, is most likely autosomal recessive retinitis pigmentosa. Rod and cone photoreceptors were reduced in numbers and outer segments were virtually absent in the region corresponding to the patient's poorest vision. In the region from approximately 20 degrees to 60 degrees (best field of vision), the outer segments of rods and cones were shortened and disorganized. The retinal pigment epithelium showed reactive changes in areas of most severe photoreceptor pathology, including re-duplication, loss of melanin, increased melanolysosomes, and migration of individual cells into the retina. The acid phosphatase reactivity of both the retinal pigment epithelium and photoreceptor cells appeared normal, as were the photoreceptor cilia and inner layers of the retina. This study thus provides improved ultrastructural documentation of a relatively early case of retinitis pigmentosa that may provide a foundation for further functional studies aimed at elucidation of this enigmatic retinal dystrophy.

Incidence of tuberous sclerosis in patients with cardiac rhabdomyoma.

Cardiac rhabdomyoma, a rare benign tumor often detected in infancy, is frequently associated with tuberous sclerosis. This association is commonly stated to occur in 50% of all cases of cardiac rhabdomyoma. Recently at our institution, the prenatal detection of a cardiac rhabdomyoma in a fetus at no known risk for tuberous sclerosis emphasized the need to determine the frequency of association in order to provide accurate diagnosis and counseling in such situations. After a review of reported cases and review of patients from our institution diagnosed to have cardiac rhabdomyoma, we estimate that 51-86% of cardiac rhabdomyomas are associated with tuberous sclerosis. We present the results of our literature and case review.

Autosomal dominant inheritance of Barber-Say syndrome.

We report on a mother-to-son transmission of the Barber-Say syndrome, a finding that strongly supports dominant inheritance of this rare disorder. The characteristic facial changes, small ears, hirsutism, and redundant skin of our patients are consistent with the findings of five reported cases. The mother also had cleft palate and mild conductive hearing loss. Her son had a shawl scrotum, primary hypospadias, and mild hearing loss by report. The inheritance of this rare disorder has not been established. The parent-to-child transmission in this family suggests X-linked or autosomal dominant inheritance. The parents of the patient reported by Santana et al. [1993: Am. J. Med. Genet. 47:20-23] were consanguineous, suggesting autosomal recessive inheritance in other cases.

Digital anomalies, microcephaly, and normal intelligence: new syndrome or Feingold syndrome?

We present four patients-two boys and their mother and an unrelated girl-with microcephaly, normal intelligence, and digital abnormalities. The hand abnormalities are characterized by brachydactyly with radial clinodactyly of the fourth and fifth fingers, ulnar clinodactyly of the second fingers, and an increased space between the second and third fingers associated with an abnormal palmar crease that extends to the ulnar border. The foot abnormalities include short toes with syndactyly of the fourth and fifth toes. The mother has normal intelligence, and her sons and the unrelated girl have normal development. Although similar digital abnormalities, microcephaly, and normal intelligence were described by Feingold in patients with gastrointestinal atresia, we think that our patients' findings represent a different condition. The most likely mode of inheritance is autosomal dominant. The clinical recognition of this syndrome will allow for appropriate genetic counseling as well as provision of information on natural history, i.e., normal intelligence.

Facio-oculo-acoustico-renal (FOAR) syndrome: case report and review.

We report on an 11-year-old boy with distinct facial anomalies, iris coloboma, iris hypoplasia, cataract, high myopia, retinal detachment, moderate sensorineural hearing loss, and proteinuria. He appears to have the facio-oculo-acoustico-renal (FOAR) syndrome, a rare familial disorder reported only 4 times previously. In contrast to the other patients, he has normal intellect.

Mother to son transmission of del(1) (q42.1q42.3).

Familial transmission of cytogenetically visible autosome deletions is rare in humans. We describe here a case of mother to son transmission of an interstitial deletion of the distal long arm of chromosome one, breakpoints q42.1q42.3. This is the smallest described deletion of this region to date.

Spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL): presentation in two unrelated patients in the United States.

This is a report of two North American patients with spondyloepimetaphyseal dysplasia with joint laxity, an uncommon autosomal recessive skeletal dysplasia rarely reported outside of South Africa. Patients with SEMDJL have vertebral abnormalities and ligamentous laxity that results in spinal misalignment and progressive severe kyphoscoliosis, thoracic asymmetry, and respiratory compromise resulting in early death. Nonaxial skeletal involvement includes elbow deformities with radial head dislocation, dislocated hips, clubbed feet, and tapered fingers with spatulate distal phalanges. Many affected children have an oval face, flat midface, prominent eyes with blue sclerae, and a long philtrum. Palatal abnormalities and congenital heart disease are also observed. Diagnosis in infancy may be difficult because many of the typical findings are not apparent early and only evolve over time. We review the physical and radiographic findings in two unrelated patients with this disorder in order to increase the awareness of this disorder, particularly for clinicians outside of South Africa.

Possible autosomal-recessive ocular coloboma.

Ocular coloboma as an isolated anomaly often is inherited as an autosomal dominant trait. Possible autosomal recessive inheritance is suggested by the presence of colobomatous malformations in a brother and sister whose parents have apparently normal eyes. Possible genetic heterogeneity of isolated ocular coloboma makes genetic counseling in sporadic cases difficult since cases may be due to autosomal dominant and autosomal recessive mutations and nongenetic causes.

Twin fetuses with abnormalities that overlap with three midline malformation complexes.

Twin fetuses aborted at an estimated gestational age of 145 days were concordant for oral, facial, skeletal, and central nervous system malformations. The twins were discordant for other anomalies including cardiac defects, polydactyly, and malrotated short bowel. The combination of malformations observed overlaps with that of the oral-facial-digital syndrome, hydrolethalus syndrome, and Pallister-Hall syndrome. The problem of phenotypic overlap between these syndromes is discussed.

Mosaic isochromosome 8p.

Findings in a patient with mosaic isochromosome 8p are compared with those of previously reported cases. There were no distinguishing findings on physical examination; all had cognitive delays, especially in speech and language development.

Partial deletion of the long arm of chromosome 11 [del(11)(q23.3----qter)] with abnormal white matter.

A patient with partial deletion of the long arm of chromosome 11[del(11)(q23.3----qter)] had macrocephalic trigonocephaly, growth and mental retardation, congenital heart defect, and characteristic facial appearance familiar to that of 33 other reported patients with this deletion. Computed tomography (CT) and magnetic resonance imaging of this infant's brain demonstrated abnormality of the supratentorial white matter. This may represent either deficiency or delay in myelination or possibly a demyelination process. No abnormalities in white matter were described in seven of 33 previously reported patients whose brains were examined by ultrasound, CT, or autopsy.

Two novel fibrillin-2 mutations in congenital contractural arachnodactyly.

Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder, comprising marfanoid habitus, flexion contractures, severe kyphoscoliosis, abnormal pinnae, and muscular hypoplasia. It is now known that mutations in the gene encoding fibrillin-2 cause CCA. Interestingly, mutations described to date cluster in the fibrillin-2 region homologous to the so-called neonatal Marfan syndrome region of fibrillin-1. Thus, it has been hypothesized that the relative infrequency of CCA compared with the Marfan syndrome is due to the limited region of the gene targeted for mutations. In support of the above hypothesis, we report here the finding of two additional FBN2 mutations in CCA, C1141F (exon 26) and C1252W (exon 29). In addition, a new 3' UTR polymorphism is also described.

Smith-Lemli-Opitz syndrome-type II: multiple congenital anomalies with male pseudohermaphroditism and frequent early lethality.

In 1964, Smith et al described a syndrome of microcephaly, growth and mental retardation, unusual facial appearance, syndactyly of toes 2 and 3, and genital abnormalities. Major structural malformations and early death have been uncommon in the many subsequent literature reports. We report on 19 infants with a phenotype we propose to call Smith-Lemli-Opitz syndrome (SLOS)-Type II, in which major structural abnormalities, male pseudohermaphroditism, and early lethality are common. Of these 19 patients, 18 had postaxial hexadactyly, 16 had congenital heart defect, 13 had cleft palate, and 10 had cataracts. Unusual findings seen in these patients at autopsy included Hirschsprung "disease" in five patients, unilobated lungs in six, large adrenals in four, and pancreatic islet cell hyperplasia in three. Comparison of our cases to 19 similar literature cases suggests the existence of a distinct phenotype that may be separate from SLOS as originally described. It is also inherited as an autosomal recessive, as documented by occurrence in one pair of sibs in this study and recurrence in three reported families.

Diagnostic criteria for Walker-Warburg syndrome.

Walker-Warburg syndrome (WWS) is an autosomal recessive disorder manifest by characteristic brain and eye malformations. We reviewed data on 21 of our patients and an additional 42 patients from the literature. From this review, we expand the phenotype to include congenital muscular dystrophy (CMD) and cleft lip and/or palate (CLP), and revise the diagnostic criteria. Four abnormalities were present in all patients checked for these anomalies: type II lissencephaly (21/21), cerebellar malformation (20/20), retinal malformation (18/18), and CMD (14/14). We propose that these comprise necessary and sufficient diagnostic criteria for WWS. Two other frequently observed abnormalities, ventricular dilatation with or without hydrocephalus (20/21) and anterior chamber malformation (16/21), are helpful but not necessary diagnostic criteria because they were not constant. All other abnormalities occurred less frequently. Congenital macrocephaly with hydrocephalus (11/19) was more common than congenital microcephaly (3/19). Dandy-Walker malformation (10/19) was sometimes associated with posterior cephalocele (5/21). Additional abnormalities included slit-like ventricles (1/21), microphthalmia (8/21), ocular colobomas (3/15), congenital cataracts (7/20), genital anomalies in males (5/8), and CLP (4/21). Median survival in our series was 9 months. A related autosomal recessive disorder, Fukuyama congenital muscular dystrophy, consists of similar but less severe brain changes and CMD. It differs from WWS because of consistently less frequent and severe cerebellar and retinal abnormalities. We think that WWS is identical to "cerebro-oculo-muscular syndrome" and "muscle, eye, and brain disease."

Simpson-Golabi-Behmel syndrome: genotype/phenotype analysis of 18 affected males from 7 unrelated families.

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked overgrowth disorder recently shown to be caused by mutations in the heparan sulfate proteoglycan GPC3 [Pilia et al., Nat Genet; 12:241-247 1996]. We have used Southern blot analysis and polymerase chain reaction amplification of intra-exonic sequences to identify four new GPC3 mutations and further characterize three previously reported SGBS mutations. De novo GPC3 mutations were identified in 2 families. In general, the mutations were unique deletions ranging from less than 0.1 kb to more than 300 kb in length with no evidence of a mutational hot spot discerned. The lack of correlation between the phenotype of 18 affected males from these 7 families and the location and size of the GPC3 gene mutations suggest that SGBS is caused by a nonfunctional GPC3 protein.

Retinitis pigmentosa.

Retinitis pigmentosa is a clinically and genetically heterogeneous group of hereditary disorders in which there is progressive loss of photoreceptor and pigment epithelial function. The prevalence of retinitis pigmentosa is between 1/3000 and 1/5000 making it one of the most common causes of visual impairment in all age groups. The natural history, differential diagnosis, diagnostic clinical and electrophysiologic findings are reviewed. Generalization about the different genetic subtypes of retinitis pigmentosa are reviewed along with the uses of DNA probes for linkage studies. Syndromes in which retinitis pigmentosa is a manifestation are summarized.