Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes.

Mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have been identified in Crouzon syndrome, an autosomal dominant condition causing premature fusion of the cranial sutures (craniosynostosis). A mutation in FGFR1 has been established in several families with Pfeiffer syndrome, where craniosynostosis is associated with specific digital abnormalities. We now report point mutations in FGFR2 in seven sporadic Pfeiffer syndrome patients. Six of the seven Pfeiffer syndrome patients share two missense mutations, which have also been reported in Crouzon syndrome. The Crouzon and Pfeiffer phenotypes usually breed true within families and the finding of identical mutations in unrelated individuals giving different phenotypes is a highly unexpected observation.

An autosomal recessive mental retardation syndrome with hepatic fibrosis and renal cysts.

Two sisters had developmental retardation and congenital hepatic fibrosis. One, 23 years old, had facial anomalies reminiscent of Smith-Lemli-Opitz syndrome, ocular coloboma, and hypoplastic kidneys with a single cyst. The other sister died at 18 months and had an encephalocele and cystically dilated collecting ducts in the renal medulla. Although the manifestations in these two sisters are similar to the Smith-Lemli-Opitz and Meckel syndromes respectively, there are sufficient differences to suggest that they had a separate autosomal recessive MCA-MR syndrome.

New case of the Carey-Fineman-Ziter syndrome.

We present a further case, the fourth known to us, of the Carey-Fineman-Ziter syndrome. The emergence of a consistent and recognisable phenotype, characterised by hypotonia, weakness, ophthalmoplegia, and a Möbius-like clinical picture, is emphasised.

Brief clinical report: neural tube defects as an X-linked condition.

We present a family in which a woman had 3 brothers and 3 sons with neural tube defects.

Joubert syndrome: a review.

We review 72 previously reported and 29 new patients with the possible diagnosis of Joubert syndrome. We define diagnostic criteria for this syndrome and present the data available in 94 patients that fulfill our criteria. We present the data regarding the clinical, neuroradiological, and ophthalmological manifestations and the prognosis of these 94 patients. We propose a classification of the patients with this diagnosis in 2 groups: those with retinal dystrophy and those without. Retinal dystrophy runs true in families and was never absent when renal cysts were reported.

Nonspecific X-linked mental retardation with macrocephaly and obesity: a further family.

The phenotypic nonspecificity of many forms of X-linked mental retardation has hampered attempts to classify them into clinically homogeneous groups. One such condition, described by Clark and Baraitser [1987: Am J Med Genet 26:13-15], has been the subject of a single pedigree report to date. We now describe a further pedigree whose affected members share many manifestations with those reported by Clark and Baraitser, and we consider the possible distinction between this condition and Atkin-Flaitz syndrome.

A syndrome of mental retardation, short stature, hemolytic anemia, delayed puberty, and abnormal facial appearance: similarities to a report of aldolase A deficiency.

We describe a brother and sister with mental retardation, short stature, delayed puberty, spherocytic anemia, and an abnormal facial appearance. The similarities to a child with aldolase A deficiency are discussed.

Distinctive syndrome of short stature, craniosynostosis, skeletal changes, and malformed ears.

We report on 2 unrelated boys with a distinctive facial appearance of microtia, atretic external auditory meati, small mandible, and microstomia, who also have a skeletal dysplasia, microcephaly, and joint contractures. The skeletal abnormalities, short stature, and microcephaly led to an initial diagnosis of osteodysplastic primordial dwarfism; however, the birth weight of one of the children is not low enough to firmly establish this diagnosis. The similarities were detected by the matching program of the London Dysmorphology Data-base.

Autosomal dominant transmission of congenital erythroid hypoplastic anemia with radial abnormalities.

We describe a mother and son with congenital hypoplastic anemia. The mother has apparently normal thumbs and forearms but her son has bilateral radial hypoplasia. They provide a further example of dominant inheritance of Diamond-Blackfan anemia/Aase syndrome and suggest that thumb and radial abnormalities are a component of this syndrome.

Proteus syndrome: an expanded phenotype.

We report on 11 new cases of Proteus syndrome to illustrate the broad range of the phenotype in this hamartomatous dysplasia. The cardinal manifestations of this sporadic disorder are hemihypertrophy, macrodactyly, exostoses, scoliosis, cavernous hemangiomas, lipomas, linear sebaceous nevi, and deeply rugated soles of the feet. Intelligence is usually normal. The differential diagnosis includes Klippel-Trenaunay-Weber and partial lipodystrophy syndromes.

Midline facial defects with ocular colobomata.

We describe 5 children with midline facial anomalies and iris colobomata reminiscent of frontonasal "dysplasia." Two patients have, in addition, abnormalities of the eyelids and one of them probably has the rare autosomal recessive condition frontofacionasal "dysplasia." The patients may have a new syndrome of midline facial defects, iris colobomata, and mental retardation.

Hemihypertrophy, hemimegalencephaly, and polydactyly.

We present clinical and neuropathological details of a patient with hemihypertrophy and hemimegalencephaly who may have Proteus syndrome. The observation of polysyndactyly in the case indicates either that polysyndactyly is a rare manifestation in Proteus syndrome, or that a separate condition, mimicking Proteus syndrome and pursuing a similar clinical course, might exist.

Male pseudohermaphroditism in sibs with the alpha-thalassemia/mental retardation (ATR-X) syndrome.

Genital abnormalities have been noted in several patients with the X-linked form of alpha-thalassemia and mental retardation syndrome (ATR-X). The initial clinical report of the condition documented a phenotypic female with 46,XY karyotype. To this we now add 2 further siblings with abnormalities of the external genitalia, manifesting as male pseudohermaphroditism.

DOOR syndrome (deafness, onycho-osteodystrophy, and mental retardation): elevated plasma and urinary 2-oxoglutarate in three unrelated patients.

We describe three further children with the DOOR syndrome (deafness, onycho-osteodystrophy and mental retardation). A severe seizure disorder and characteristic facial appearance are part of the syndrome. Fourteen similar cases including the present patients are now on record. Autosomal recessive inheritance is likely. An increased level of 2-oxoglutarate in both plasma and urine has been found in our three patients. It is suggested there may be an inherited metabolic defect in this malformation syndrome.

Genetic and clinical heterogeneity of Stickler syndrome.

We have studied 6 multigeneration Stickler syndrome families. Manifestations of the syndrome in the families included myopia, deafness, arthritis, characteristic facial changes with "flat" midface and cleft palate, although not all these were present in all families. COL2A1 has been implicated as a gene which can give rise to Stickler syndrome based on evidence from 2 large families which each showed significant linkage between the disease locus and restriction fragment length polymorphisms for the gene (Francomano CA, Lieberfarb RM, Hirose T, Maumenee IH, Streeten EA, Meyers DA, Pyeritz RE (1987): Genomics 1:293-296; Knowlton RG, Weaver EJ, Struyk AF, Knobloch WH, King RA, Norris K, Shamban A, Uitoo J, Jimenez SA, Prockop DJ (1989): Am J Hum Genet 45:681-688). We have found crossovers between the disease locus and COL2A1 in 2 families with Stickler syndrome. This could be explained by either genetic heterogeneity or the actual mutation being in a closely linked, currently unrecognized gene. We found a weakly positive overall lod score (z = 0.96 at theta = 0.10) suggesting that genetic heterogeneity is a more likely explanation. In one family, with typical findings, a translocation t5;17 (q15:q23) was found to segregate with the disease in 4 affected relatives. In view of the possible heterogeneity, although no crossovers with COL2A1 were seen in this family, either of these breakpoints could be the position of a further disease causing gene.

The Weissenbacher-Zweymüller, Stickler, and Marshall syndromes: further evidence for their identity.

We report on three unrelated children with neonatal radiological characteristics of the Weissenbacher-Zweymüller (W-Z) syndrome. Subsequently, they developed the Marshall syndrome. The relationship between the W-Z, Marshall, and Stickler syndromes is discussed.

Mesomelic limb shortness: a previously unreported autosomal recessive type.

We report on sibs, the offspring of a consanguineous mating, whose mesomelic shortness and bowing of limbs with associated skin dimpling, retrognathia, mandibular hypoplasia, cleft palate, and camptodactyly represents a previously apparently unreported syndrome. The radiological findings are discussed, particularly with regard to the main known diagnostic possibilities.

Autosomal recessive congenital intrauterine infection-like syndrome of microcephaly, intracranial calcification, and CNS disease.

We present data on 10 patients from 5 families with a condition of microcephaly, intracranial calcification, and a clinical course resembling congenital TORCH infection. Repeatedly, negative TORCH investigations are a prerequisite for the identification of this disorder and the value of disturbed liver function and thrombocytopenia as aids to diagnosis is emphasised. Several similar families with recurrence of the disease in sibships are identified in the literature and the genetic implications of our observations are considered.

A gene for FG syndrome maps in the Xq12-q21.31 region.

FG syndrome is an X-linked recessive condition in which mental retardation is associated with congenital hypotonia, macrocephaly, characteristic face, and constipation. This syndrome was mapped by Zhu et al. [Cytogenet Cell Genet 1991;58:2091A] to Xq21.31-q22 by linkage analysis with a max lod score of 1.2 for the DXYS1X, DXS178, DXS101, and DXS94 loci and crossovers at DXS16 (Xp22.31) and DXS287 (Xq22.3). However, this mapping was only provisional and needed to be refined. In this paper, we report the results of a new linkage analysis performed on 10 families including that studied by Zhu et al. [1991]. Two-point analysis demonstrated linkage with DXS441 (Zmax = 3.39 at theta = 0.12) at Xq13. In addition, separate analysis of the lod scores obtained for the Xq13 markers suggested linkage exclusion for three families. Genetic heterogeneity was confirmed by analysis of the linkage results with the HOMOG program (max logL = 4.07, theta = 0, alpha = 0.65). Localization of one FG gene between DXS135 and DXS1066 was suggested by analysis of crossovers found in those three families which were assumed to be linked to Xq13 with a probability of 0.95 or more. This region could be reduced to the DXS135-DXS72 interval after combining our data with those from deletions previously described in males in the Xq13-q21 region.

Axonal velocities of motor units in the hand and foot muscles of the baboon.

The axonal velocities of single motor units in the small hand and foot muscles of the baboon were studied by means of a collision technique which produced selective blocking of most of the fast-conducting fibres. In the abductor pollicis brevis muscle velocities ranged from 43 to 82 m/sec, and in the abductor digiti minimi muscle from 40 to 78 m/sec. In the extensor digitorum brevis muscle the range was 40-70 m/sec. When velocities were plotted as percentages of the maximal obtained in the same experiment, the range was similar in the 3 muscles studied. Most motor units had velocities greater than 65% of maximal but, in a few, velocities were between 55% and 65% of maximal. The possible relevance of these findings to human motor nerves is discussed.