Sixteenth-century German woodcut of a male infant with possible disorganization.

History has preserved a beautiful 16th century woodcut print, which depicts an infant with several malformations. The German inscription describes the infant's hypotonia and ectopic growths, and the image itself shows a child with an ectopic accessory third lower limb, a large papilla, and an omphalocele-like growth. The 'case' bears striking similarity to reported human cases of the disorganization (Ds) syndrome. This article describes the woodcut, describes Ds, and then explains how the image may represent the earliest depiction of Ds in history.

A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome.

Pfeiffer syndrome (PS) is one of the classic autosomal dominant craniosynostosis syndromes with craniofacial anomalies and characteristic broad thumbs and big toes. We have previously mapped one of the genes for PS to the centromeric region of chromosome 8 by linkage analysis. Here we present evidence that mutations in the fibroblast growth factor receptor-1 (FGFR1) gene, which maps to 8p, cause one form of familial Pfeiffer syndrome. A C to G transversion in exon 5, predicting a proline to arginine substitution in the putative extracellular domain, was identified in all affected members of five unrelated PS families but not in any unaffected individuals. FGFR1 therefore becomes the third fibroblast growth factor receptor to be associated with an autosomal dominant skeletal disorder.

Opitz syndrome is genetically heterogeneous, with one locus on Xp22, and a second locus on 22q11.2.

Opitz syndrome (OS, McKusick 145410) is a well described genetic syndrome affecting multiple organ systems whose cardinal manifestations include widely spaced eyes and hypospadias (Fig. 1). It was first reported as two separate entities, BBB syndrome, and G syndrome. However, subsequent reports of families in which the BBB and G syndrome segregated within a single kindred suggested that they were a single clinical entity. Although the original pedigrees were consistent with X-linked and autosomal dominant inheritance, male-to-male transmission in subsequent reports suggested that OS was inherited as an autosomal dominant trait. Here we report that OS is a heterogeneous disorder, with an X-linked and an autosomal locus. Three families were linked to DXS987 in Xp22, with a lod score of 3.53 at zero recombination. Five families were linked to D22S345 from chromosome 22q11.2, with a lod score of 3.53 at zero recombination. This represents the first classic multiple congenital anomaly syndrome with an X-linked and an autosomal form.

Pendular nystagmus in patients with peroxisomal assembly disorder.

BACKGROUND: Pendular nystagmus commonly occurs in congenital and acquired disorders of myelin. OBJECTIVE: To characterize the nystagmus in 3 siblings with an infantile form of an autosomal recessive peroxisomal assembly disorder causing leukodystrophy. DESIGN: We examined visual function and measured eye movements using infrared oculography. We noted changes in eye speed and frequency before and after the administration of gabapentin to 1 patient. RESULTS: All 3 siblings showed optic atrophy and pendular nystagmus that was predominantly horizontal, at a frequency of 3 to 6 Hz, with phase shifts of 45 degrees to 80 degrees between the oscillations of each eye. Gabapentin administered to 1 child caused a modest improvement of vision and the reduction of the velocity and frequency of oscillations in the eye with worse nystagmus. CONCLUSION: The pendular nystagmus in these patients was due to their leukodystrophy and may have a similar pathogenesis to the oscillations seen in other disorders affecting central myelin.

Severe oculocerebrocutaneous (Delleman) syndrome: overlap with Goldenhar anomaly.

Oculocerebrocutaneous syndrome (OCCS), or Delleman syndrome, is a multiple congenital anomaly syndrome characterized by orbital cysts, cerebral malformations, and focal dermal hypoplasia [Delleman and Oorthuys, 1981, Clin Genet 19:191-198; Delleman et al., 1984, Clin Genet 25:470-472]. Two previous reports presented children having what is suggested as the more severe form of the OCCS syndrome who also had anophthalmia, congenital hydrocephalus, and cleft lip and palate [Leichtman et al., 1994, Am J Med Genet 50:39-41; Angle and Hersh, 1997, Am J Med Genet 68:39-42]. We report on a third case of severe OCCS, an infant girl with a similar constellation of findings and additional anomalies including lateral facial cleft, vertebral anomaly, and ventricular septal defect. The additional findings in our patient highlight the phenotypic overlap of OCCS and the Goldenhar anomaly, an overlap previously noted by Delleman and Oorthuys [1981], and others [Al-Gazali et al., 1988, J Med Genet 25: 773-778]. We suggest that the minimal diagnostic criteria for Delleman syndrome include central nervous system cyst or hydrocephalus, orbital cysts or microphthalmia, and focal skin defects.

Disorganization in mice and humans.

Disorganization (Ds) is an autosomal dominant mouse mutant that produces a remarkable array of birth defects. So variable is the phenotype that no two mice appear identical. Ds also has markedly reduced penetrance, with 85-99% of Ds mice having no apparent anomalies. Paired structures are often affected, but always asymmetrically. Although the Ds gene has yet to be identified, it is thought that Ds is a gain-of-function mutation, and that Ds malformations are thought to arise through a two-hit mechanism. Unlike the two-hit model that has been used to describe the development of retinoblastoma, the "second hit" for Ds is thought not to arise in the other Ds allele. Although there is a long list of anomalies seen in Ds mice, two stand out as most characteristic: hamartomatous skin papillae, and mirror-image limb duplications. Through the observation of these unusual anomalies in human cases, the possibility of a human homologue of Ds was suggested. However, in reviewing types of anomalies seen in Ds mice, it is apparent that cases with these unusual defects represent only one end of the spectrum of the Ds phenotype. Ds may be the genetic basis for more usual and seemingly sporadic human birth defects as well.

Disorganization in mice and humans and its relation to sporadic birth defects.

Disorganization (Ds) is a mouse mutant best known for producing an exceptional variety of unusual developmental anomalies, such as mirror-limb duplications and hamartomatous skin papillae. So great is the range of malformations that no two affected mice are identical. Several patients with a similar variety of exceptional anomalies have been reported, raising the possibility of the existence of a human homologue of Ds. However, although these human cases represent the most striking findings seen in Ds mice, they do not represent the full range of defects. Most affected mice have only a single malformation, and most of these malformations are similar to both common (neural tube defects, orofacial clefting, gastroschisis, limb reductions) and rare (anophthalmia, duplicated rectum) human birth defects. It is therefore possible that the full spectrum of the human homologue of Ds includes not only patients with the unusual combination of anomalies but also common sporadic birth defects. We suggest that the low penetrance (approximately 0-30%) and highly variable expression of Ds make it a paradigm for understanding the genetic basis for many seemingly sporadic birth defects.

Sibs with cleidocranial dysplasia born to normal parents: germ line mosaicism?

Cleidocranial dysplasia (CCD) is classically an autosomal dominant disorder. However, the possibility of an autosomal recessive form of CCD has been suggested based on a report of 2 consanguineous families, one with a single affected child, the second with affected sibs, born to normal parents. We present a family with sibs with CCD born to normal parents, and suggest germ line mosaicism as the more likely mechanism for this occurrence.

Duplication 14(q24.3q31) in a father and daughter: delineation of a possible imprinted region.

A number of clinical reports have described children with a variety of congenital anomalies in association with uniparental disomy (upd) of chromosome 14, suggesting that at least some genes on chromosome 14 are subject to parent of origin, or imprinting, effects. However, little else is known about this putative imprinting of chromosome 14. Both maternal and paternal upd have been observed, but a consistent phenotype has only been suggested for the former. Here we report on a child with developmental delay, microcephaly, distinct facial findings, and who has a duplication of 14q24.3q31. The same cytogenetic abnormality was found in her phenotypically normal father. We hypothesize that this segment of chromosome 14 contains maternally silenced genes, and that this duplicated segment defines an imprinted region on chromosome 14. Alternatively, this cytogenetic duplication may be unrelated to the girl's phenotypic anomalies, and this duplication may contain genes that are not subject to dosage effect.

Craniosynostosis, Philadelphia type: a new autosomal dominant syndrome with sagittal craniosynostosis and syndactyly of the fingers and toes.

The acrocephalosyndactyly syndromes (ACS) are a group of clinically similar disorders that share the manifestations of craniosynostosis and a variety of hand and foot anomalies. Here we report on a 5-generation kindred segregating sagittal craniosynostosis and syndactyly of the fingers and the toes in an autosomal dominant manner. The anomalies seen in this kindred comprise a syndrome distinct from other craniosynostosis syndromes. For this novel syndrome, we propose the name craniosynostosis, Philadelphia type.

Microcephaly-lymphedema-chorioretinal dysplasia: a unique genetic syndrome with variable expression and possible characteristic facial appearance.

We report on a follow-up examination of a family with microcephaly and lymphedema. The finding of chorioretinal dysplasia with variable visual deficit in multiple relatives, which was not previously discovered, supports the concept of microcephaly, lymphedema, and chorioretinopathy as being a single autosomal dominant genetic entity with variable expression. We recommend that fundoscopic examination be performed in all patients with microcephaly with or without lymphedema.

Child with mosaic variegated aneuploidy and embryonal rhabdomyosarcoma.

We report on a 7-year-old boy with mosaic variegated aneuploidy (MVA) who developed embryonal rhabdomyosarcoma of the soft palate. This patient is the 11th case report of MVA and represents further documentation of the true existence of this rare mitotic mutant. Clinical findings share similarities to those previously described patients including microcephaly and growth retardation as the two most common abnormalities. Notably, mental retardation is not universally present. Results of serial cytogenetic analyses performed on somatic and neoplastic tissues are reviewed and compared with those of other previously reported patients. We postulate that mosaic variegated aneuploidy is causally related to the development of rhabdomyosarcoma in our patient. This is the first report of a patient with MVA who developed cancer and suggests that these patients may be at risk for malignancy and require long-term follow-up and cancer surveillance.

Clinical and molecular studies of brachydactyly type D.

We report on the clinical manifestations in six affected individuals from a four-generation family that segregates brachydactyly type D (BDD). All affected individuals have either bilateral and symmetric or unilateral first distal phalangeal hypoplasia. Metacarpal-phalangeal profiles show that some affected individuals also have a more generalized involvement of the apical skeleton. However, other than first distal phalangeal hypoplasia, there is no consistent pattern of associated skeletal involvement. Linkage analyses were preformed between the BDD phenotype in this family and six loci known to contain genes involved in apical skeletal patterning. No statistically significant linkage was detected.

Adult with an interstitial deletion of chromosome 10 [del(10)(q25. 1q25.3)]: overlap with Coffin-Lowry syndrome.

We recently evaluated a mentally retarded 48 year old man found to have a cytogenetic deletion of chromosome 10 [46,XY,del(10) (q25. 1q25.3)]. Of interest, he shares many clinical findings with those described in Coffin-Lowry syndrome (CLS). These include severe mental retardation, short stature and a coarse facial appearance with widely spaced eyes, and patulous lips. He also had an extra transverse hypothenar crease, a finding that is seen in CLS. Furthermore, he has characteristic radiographic hand findings described in 95% of patients with CLS. The CLS gene, located at Xp22. 2, has recently been identified, and mutations in the Rsk-2 gene have been identified in several CLS patients. Rsk2 is part of a gene family implicated in cell cycle regulation through the mitogen-activated protein (MAP) kinase cascade. None of the currently recognized components of this pathway maps to the region deleted in our patient, nor are we able to identify any likely candidate genes in the deleted region, although several G protein coupled receptors have been cloned from the region. This patient's findings have some overlap with those seen in CLS, suggesting that a gene involved in MAP kinase signaling may be present in the deleted region of chromosome 10q25.1-25.3. Patients with a phenotype consistent with CLS, but lacking a family history suggestive of an X-linked disorder, should be evaluated with chromosome analysis paying particular attention to the region 10q25.

Distal 5q deletion syndrome: phenotypic correlations.

We describe the phenotypes of two male sibs with partial monosomy of chromosome 5 [46,XY,der(5)inv ins(1;5)(p32;q35.4q34)]; maternally derived from a balanced insertion of 1 and 5 [inv ins (1;5)(p.32;q35.4q34)]. One sib had microcephaly, cleft lip and palate, facial anomalies, atrial (ASD) and ventricular (VSD) septal defects, camptodactyly 4th and 5th fingers, and developmental delay. The other sib showed microcephaly, facial anomalies, ASD, hypotonia, primary optic nerve hypoplasia, and developmental delay. Only seven other patients with 5q deletions distal to 5q33 have been reported and none showed the putative breakpoints identified in our two patients. All nine showed developmental delay or malformations of the CNS and facial anomalies; six of nine had defects of cardiac septation. Our two patients and one other were shown to have only one copy of the cardiac specific hCSX gene that defines in part the etiology of their ASD and VSD. The other components of their phenotypes cannot be related at present to genes identified in the deleted segments.

Clinical and locus heterogeneity in brachydactyly type C.

Brachydactyly type C is characterized by shortness of the second and fifth middle phalanges and the first metacarpal. It is inherited as an autosomal dominant trait, and is noted for its widely variable clinical phenotype both within and between families. In most families involvement is limited to the hands. However, in some families additional skeletal and non-skeletal findings have been reported. We report on 12 affected members from a 5 generation kindred that segregates a brachydactyly type C phenotype. All affected individuals had shortness principally affecting the second and fifth phalanges and first metacarpal. However, the metacarpal-phalangeal profile indicated that other digital elements were short as well. In addition, one affected individual had a bilateral Madelung deformity, but none had foot involvement. No other non-skeletal findings cosegregated with brachydactyly in this family. Recently, a gene for brachydactyly type C has been localized to 12q24. This was done by studying a large kindred first reported by Haws [1963], which manifests both hand and foot anomalies. Here we present linkage data which excludes the 12q24 locus in our kindred, indicating locus heterogeneity as one explanation for the interfamilial variability described in brachydactyly type C.

Syntelencephaly in an infant of a diabetic mother.

Here we report on an infant of a diabetic mother (IDM) with midline interhemispheric "fusion" (MIF), or syntelencephaly. This is a rare anomaly characterized by segmental failure of cleavage of the cerebral hemispheres and other brain structures in the posterior frontal and parietal regions, with a normal interhemispheric fissure anterior and posterior to the "fused" region. While there is obvious overlap with holoprosencephaly (HPE), this condition differs from HPE in that the midline "fusion" in MIF is complete but segmental, while the structural brain anomalies seen in the HPE spectrum progress smoothly in severity in a posterior to anterior "fusion." However, while it is apparent that there are key distinctions between MIF and HPE, in all likelihood they arise from a similar pathogenetic mechanisms. We therefore suggest that MIF is a distinct variant of the HPE spectrum of midline brain anomalies. Given the known increased incidence of HPE in IDMs, MIF is likely a maternal diabetes-associated malformation.

New finding of Schinzel-Giedion syndrome: a case with a malignant sacrococcygeal teratoma.

We report on a boy with Schinzel-Giedion syndrome (SGS) with a previously unreported manifestation, a malignant sacrococcygeal teratoma. This is the second case of SGS to have a malignancy, as one earlier case had a hepatoblastoma. We postulate that the occurrence of 2 uncommon embryonic tumors among these patients with a rare syndrome may mean that risk of malignancy may be a component of this syndrome.

Favorable prognosis for children with Pfeiffer syndrome types 2 and 3: implications for classification.

Pfeiffer syndrome (PS) is an autosomal dominant condition comprising bilateral coronal craniosynostosis, midface hypoplasia with a beaked nasal tip, and broad and medially deviated thumbs and great toes. It is a clinically variable disorder and has been divided into three subtypes [Cohen, 1993: Am J Med Genet 45:300-307]. Type 1 represents the less severe cases, while types 2 and 3 are the more severe cases. These latter types tend to have a higher risk for neurodevelopmental problems and a reduced life expectancy. Here we review the clinical course of seven children with PS type 3. All of these children had severe manifestations of PS; however, development was essentially normal in three, mild delay was noted in two, and moderate delay in one. Favorable outcomes in children with types 2 and 3 PS were also documented by Moore et al. [1995: Cleft Pal-Craniofac J 32:62-70]. These cases illustrate that while children with PS types 2 and 3 have an increased risk for neurodevelopmental difficulties, a favorable outcome can be achieved in some cases with aggressive medical and surgical management. Finally, although such management should be the rule for PS types 2 and 3, it needs to be remembered that normal outcome is not the rule. The prognosis for favorable neurodevelopmental outcome and/or life expectancy remains guarded in most cases.