A translocation interrupts the COL5A1 gene in a patient with Ehlers-Danlos syndrome and hypomelanosis of Ito.

Ehlers-Danlos syndrome (EDS) is a genetically and pathogenetically heterogeneous group of disorders of which at least 11 types have been described. All are connective tissue disorders characterized by defects of the skin, ligaments and blood vessels with the clinical spectrum ranging from innocuous findings to lethality. Mutations in the genes encoding the major fibrillar collagen types I and III have been demonstrated in EDS types VII and IV, respectively, while mutations in the lysyl hydroxylase and ATP7A genes, with roles in collagen cross-linking, are responsible for EDS types VI and IX. The biochemical and molecular bases for the most common forms of EDS (types I, II and III) are unknown. Here, we describe a balanced translocation between chromosome 9 and an X chromosome that disrupts the minor fibrillar collagen type V gene COL5A1 in a patient with both EDS type I and hypomelanosis of Ito. The breakpoint occurs at 9q34 within COL5A1 intron 24 and interestingly, within a LINE-1 (L1) element at Xp21.1. A fusion mRNA between COL5A1 and an Alu sequence is produced, but no aberrant protein is detectable. Rather, the amount of type V collagen is reduced in the patient's fibroblasts, suggesting haploinsufficiency as a cuase of the phenotype. This demonstrates that a mutation in a type V collagen gene, COL5A1, results in EDS type I, and shows the involvement of L1 sequences in a constitutional chromosomal translocation. Because collagen type V is a heteromorphic protein in which molecules may be composed of polypeptides encoded by three COL5A genes, this suggests all three genes as candidates for mutations in EDS.

Toriello-Carey syndrome in a patient with a de novo balanced translocation [46,XY,t(2;14)(q33;q22)] interrupting SATB2.

Toriello-Carey syndrome (TCS; OMIM 217980) is a multiple congenital anomaly syndrome characterized by the common manifestations of corpus callosum agenesis, cardiac defects, cleft palate/Robin sequence, hypotonia, mental retardation, postnatal growth retardation and distinctive facial dysmorphology (including micrognathia, telecanthus, small nose and full cheeks). Both autosomal recessive and X-linked inheritance have been proposed, but chromosomal abnormalities involving disparate loci have also been detected in a small number of cases. We report a patient with classical features of TCS and an apparently balanced de novo translocation between chromosomes 2 and 14 [46,XY,t(2;14)(q33;q22)]. Molecular characterization revealed direct interruption of the special AT-rich sequence-binding protein-2 (SATB2) gene at the 2q33.1 translocation breakpoint, while the 14q22.3 breakpoint was not intragenic. SATB2 mutation or deletion has been associated with both isolated and syndromic facial clefting; however, an association with TCS has not been reported. SATB2 functions broadly as a transcription regulator, and its expression patterns suggest an important role in craniofacial and central nervous system development, making it a plausible candidate gene for TCS.

Novel autosomal dominant mandibulofacial dysostosis with ptosis: clinical description and exclusion of TCOF1.

BACKGROUND: Treacher Collins syndrome (TCS), the most common type of mandibulofacial dysostosis (MFD), is genetically homogeneous. Other types of MFD are less common and, of these, only the Bauru type of MFD has an autosomal dominant (AD) mode of inheritance established. Here we report clinical features of a kindred with a unique AD MFD with the exclusion of linkage to the TCS locus (TCOF1) on chromosome 5q31-q32. METHODS: Six affected family members underwent a complete medical genetics physical examination and two affected subjects had skeletal survey. All available medical records were reviewed. Linkage analysis using the markers spanning the TCOF1 locus was performed. One typically affected family member had a high resolution karyotype. RESULTS: Affected subjects had significant craniofacial abnormalities without any significant acral changes and thus had a phenotype consistent with a MFD variant. Distinctive features included hypoplasia of the zygomatic complex, micrognathia with malocclusion, auricular abnormalities with conductive hearing loss, and ptosis. Significantly negative two point lod scores were obtained for markers spanning the TCOF1 locus, excluding the possibility that the disease in our kindred is allelic with TCS. High resolution karyotype was normal. CONCLUSIONS: We report a kindred with a novel type of MFD that is not linked to the TCOF1 locus and is also clinically distinct from other types of AD MFD. Identification of additional families will facilitate identification of the gene causing this type of AD MFD and further characterisation of the clinical phenotype.

Arrested epidermal morphogenesis in three newborn infants with a fatal genetic disorder (restrictive dermopathy).

Two sibs and one unrelated infant were born prematurely with taut, shiny, restrictive skin that was abnormal in structure, organization, biochemistry, and state of differentiation. Prominent abnormalities in all regions of the skin were recognized by light and electron microscopy, immunohistochemistry, and biochemistry. The epidermis was hyperplastic, hyperkeratotic, and parakeratotic. Keratohyaline granules were abnormal in structure, but the keratohyalin-derived protein filaggrin was apparently normal in quantity and biochemistry. The epidermal cells contained less than the expected quantity of high-molecular-weight, differentiation-specific keratins and the tissue stained with antikeratin antibodies in an aberrant pattern. Additional 48 and 56 kD keratin polypeptides, indicative of a hyperproliferative state, were expressed. The dermal-epidermal junction was remarkably flat and the dermis was thinner than normal. The connective tissue appeared stretched and was oriented like tendon rather than dermis. Collagen fiber bundles and fibrils were smaller in diameter than normal. The nails were normal but other epidermal appendages such as the pilosebaceous structures and the eccrine sweat glands were underdeveloped, suggesting that morphogenesis of these structures was arrested at an early stage in utero. The subcutaneous fat was at least twice the thickness of the dermis. The skin abnormalities appeared to be the cause of the flexion contractions, characteristic facies, and inability to survive because of restricted respiratory movements. The structural and biochemical abnormalities in the skin of affected infants may serve as markers for prenatal and postnatal diagnosis of the disorder, and may provide insight into the basic mechanism of the disease.

Craniodigital syndromes: report of a child with Filippi syndrome and discussion of differential diagnosis.

We describe a boy with low birth weight, congenital microcephaly, multiple minor facial anomalies, cleft palate, soft tissue syndactyly of fingers and toes, and moderate to severe mental retardation. Literature review suggested 6 possible diagnoses, including Scott craniodigital syndrome, Chitayat syndrome, Filippi syndrome, Zerres syndrome, Kelly syndrome, and Woods syndrome. Each has as part of the phenotype craniofacial anomalies and soft tissue syndactyly of fingers and toes; and superficially, distinction among the 6 may be difficult. However, based on the phenotype analysis we performed, we conclude that our patient has Filippi syndrome, and thus is the first reported case from the United States.

Corpus callosum agenesis, facial anomalies, Robin sequence, and other anomalies: a new autosomal recessive syndrome?

We describe findings in four children, three of whom are sibs, who appear to have the same, previously undescribed multiple congenital anomaly (MCA) syndrome. The main manifestations include agenesis of the corpus callosum, telecanthus, short palpebral fissures, small nose with anteverted nares, Robin sequence, abnormal ears, redundant neck skin, laryngeal anomalies, cardiac defect, short hands, and hypotonia. The presence of this condition in sibs of each sex suggests that autosomal recessive inheritance is the most likely cause.

Occurrence of neural tube defects among first-, second-, and third-degree relatives of probands: results of a United States study.

Data on the occurrence of neural tube defects in first-, second-, and third-degree relatives of probands were collected in a United States study. The proportions of affected individuals were 3.2%, 0.5%, and 0.17% respectively. These findings are compared to those from other recent North American studies, and differences are discussed. It is pointed out that accurate recurrence risk figures may not be available, and that caution should be used when counseling families with relatives who are affected with NTD.

Apparently new MCA/MR syndrome in sibs with cleft lip and palate and other facial, eye, heart, and intestinal anomalies.

We report on a sister and brother with severe mental retardation, bulbous tip of the nose, long columella, cleft lip and palate, heart and intestinal anomalies, and growth retardation. This appears to be a previously unreported, autosomal recessive condition, given high resolution prometaphase chromosomes are normal.

Possible causal heterogeneity in spina bifida cystica.

A study was performed to determine whether causal heterogeneity can be demonstrated among the nonsyndromal spina bifida cysticas based on the vertebral level of the defect. Two groups were compared, probands with defects at or above T 11, likely representing defects of neuralization, and probands with defects at or below T 12, likely defects of canalization. Differences between the two groups were found with respect to reproductive history and occurrence of other malformations. A high degree of concordance for the type of defect among affected sib pairs was also observed. These findings indicate that there is probably heterogeneity within the spina bifida cysticas based on the level of the defect.

Bilateral pulmonary agenesis: association with the hydrolethalus syndrome and review of the literature from a developmental field perspective.

Only a few cases of bilateral pulmonary agenesis have been reported. Recently we saw such a case in an infant with the hydrolethalus syndrome. This observation seems to indicate that bilateral pulmonary agenesis is a severe expression of a developmental field defect that usually is represented by abnormal lung lobation or hypoplasia. The previously reported cases are discussed from the perspective of the developmental field concept.

X-linked midline defects.

Opitz and Gilbert [Am J Med Genet 12:443-455, 1982] have postulated that the midline may be a kind of developmental field. Although developmental field defects (primary malformations) usually occur sporadically, in some instances they can be caused by a single gene mutation. We report on a family in which the occurrence of midline defects was consistent with X-linked inheritance. Anomalies present in the family include hydrocephalus, anencephaly, cleft lip, congenital heart defect, renal agenesis, and hypospadias.

Provisionally unique autosomal recessive chondrodysplasia punctata syndrome.

Stippled epiphyses occur in several monogenic, teratogenic, or aneuploidy syndromes. We describe two sibs with a provisionally unique chondrodysplasia punctata syndrome, who have, in addition to stippled epiphyses, minor facial anomalies, short stature, and ocular colobomata. Inheritance of this condition is likely autosomal recessive.

Congenital pulmonary lymphangiectasia and other anomalies in a child: provisionally unique syndrome?

Congenital pulmonary lymphangiectasis is a rare anomaly that is causally heterogeneous. It can occur as either an isolated finding or one manifestation of several multiple congenital anomaly syndromes. We describe a child with congenital pulmonary lymphangiectasis and the anomalies who likely has a provisionally unique condition.

Brief communication: possible X-linked anencephaly and spina bifida--report of a kindred.

Causal heterogeneity of anencephaly and spina bifida has been demonstrated; in rare families the neural tube defect may be caused by a single gene. We report a family in which four cases of anencephaly or spina bifida may represent X-linked inheritance.

Two siblings with Tel Hashomer camptodactyly and mitral valve prolapse.

A brother and sister with Tel Hashomer camptodactyly and mitral valve prolapse are described. Mitral valve prolapse is heterogenous, but appears to occur more frequently in individuals with connective tissue disorders. The presence of mitral valve prolapse as a component manifestation of Tel Hashomer camptodactyly suggests that abnormal connective tissue is a pleiotropic effect of the mutant allele.

Renal tubular dysgenesis: delayed onset of oligohydramnios.

Two premature sibs had Potter sequence and died of respiratory failure within the first day. Ultrasonography at 26 weeks during the earlier of the two pregnancies showed complete absence of amniotic fluid, and the urinary bladder was not visualized. Ultrasound examinations during the second pregnancy showed adequate amniotic fluid at 16 and 20 weeks, with a subsequent reduction in fluid volume. Two older sibs had also died of respiratory failure shortly after birth. Postmortem histopathologic studies showed all four sibs to have severely deficient renal tubular development. However, the presence of numerous glomeruli indicated prolific nephrogenesis. Most of the tubules in sections of cortex had the lectin-binding and immunohistochemical characteristics of collecting ducts; proximal tubules were not identified by lectin-binding. Electron-microscopic examination showed a general absence of differentiated characteristics in cortical tubular epithelium, except that rare tubules contained rudimentary proximal tubular brush borders. Three of the sibs were boys, one a girl. The three children that were studied had normal chromosomes. Two unaffected sibs are alive and well. Neither parent has any clinical evidence of renal disease. These studies support the interpretation that renal tubular dysgenesis is autosomal recessive with pleiotropy. However, the relatively late appearance of oligohydramnios makes early diagnosis difficult, even when the condition is suspected.

Autosomal recessive syndrome of sacral and conotruncal developmental field defects (Kousseff syndrome).

Kousseff [1984] reported on three sibs with an autosomal recessive syndrome of sacral meningocele, conotruncal heart defects, and minor anomalies of head and neck. We report on a fourth case and discuss the findings from a developmental field perspective and the ramifications for genetic counseling.

Sibs with the fetal akinesia sequence, fetal edema, and malformations: a new syndrome?

Pena and Shokeir [J Pediatr 85:373-375. 1974] first described a syndrome characterized by multiple ankyloses, camptodactyly, facial anomalies, and pulmonary hypoplasia, which was later termed Pena-Shokeir I syndrome. Recent evidence suggests that a more accurate designation for this condition is the fetal akinesia sequence, which is almost certainly a heterogeneous entity. We describe sibs who were diagnosed as having Pena-Shokeir I syndrome but who did not have the muscular or anterior horn cell changes characteristic of other infants with the fetal akinesia sequence. In addition, both sibs had fetal edema, the first sib had coarctation of the aorta, and the second had polydactyly and thyroid hypoplasia. We suggest that this case provides further evidence for heterogeneity in the fetal akinesia sequence and may represent a provisionally unique syndrome.

Familial occurrence of a developmental defect of the medial nasal processes.

We report on a family in which the propositus and two distant relatives have a wide nose, broad philtrum, and short columella, a fusion defect of the medial nasal processes. This anomaly resembles potato nose [Benjamins and Stibbe, Acta Otolaryngol 11:274-284, 1927] and bifid nose [Anyane-Yeboa et al, Am J Med Genet 17:561-563, 1984], which are also fusion anomalies of the medial nasal processes. Potato nose is an autosomal dominant trait, whereas bifid nose is likely heterogeneous. In this family autosomal recessive inheritance is likely, therefore suggesting that anomalies of the medial nasal processes are causally heterogeneous and represent a developmental field defect.

Scalp and limb defects with cutis marmorata telangiectatica congenita: Adams-Oliver syndrome?

We report on a boy with congenital scalp and limb defects, consistent with a diagnosis of Adams-Oliver syndrome (aplasia cutis congenita with terminal transverse limb defects). An additional finding present in this child and in his mother was cutis marmorata telangiectatica congenita. Although this boy fits the diagnostic criteria for Adams-Oliver syndrome, his mother does not. We discuss whether this condition is highly variable, or heterogeneous.