Evidence for digenic inheritance in some cases of Antley-Bixler syndrome?

The Antley-Bixler syndrome has been thought to be caused by an autosomal recessive gene. However, patients with this phenotype have been reported with a new dominant mutation at the FGFR2 locus as well as in the offspring of mothers taking the antifungal agent fluconazole during early pregnancy. In addition to the craniosynostosis and joint ankylosis which are the clinical hallmarks of the condition, many patients, especially females, have genital abnormalities. We now report abnormalities of steroid biogenesis in seven of 16 patients with an Antley-Bixler phenotype. Additionally, we identify FGFR2 mutations in seven of these 16 patients, including one patient with abnormal steroidogenesis. These findings, suggesting that some cases of Antley-Bixler syndrome are the outcome of two distinct genetic events, allow a hypothesis to be formulated under which we may explain all the differing and seemingly contradictory circumstances in which the Antley-Bixler phenotype has been recognised.

Severe microcephaly, choreiform movements, cataracts and sensorineural deafness in two patients: a new syndrome?

Two unrelated male patients are described with severe microcephaly, early-onset choreiform movements, cataracts, sensorineural deafness and profound developmental delay. Our patients have much in common with the three male siblings described by Tomiwa et al., who also had cataracts, deafness and developmental delay, but much less severe microcephaly and a different type of movement disorder with later onset [Tomiwa K et al. (1987). Neuropediatrics 18:231-234]. An extensive literature search did not reveal any other reports of patients with a similar condition. We discuss the differential diagnosis.

Frontonasal dysplasia with optic disc anomalies and other midline craniofacial defects: a report of six cases.

The association of optic disc abnormalities with basal encephaloceles, specifically of the sphenoethmoidal type, and midline facial clefts has rarely been reported, although the association of midline facial clefts with encephaloceles is well described. We now report six cases of children, three males and three females, presenting with a sphenoethmoidal encephalocele, optic disc anomalies, midline facial clefting, hypertelorism, complete or partial agenesis of the corpus callosum, and endocrinological disturbances, including diabetes insipidus and pituitary dysfunction. This report underlines the importance of careful ophthalmic and endocrinological investigation of children with midline clefts associated with basal encephaloceles. These cases may represent a distinct entity within the spectrum of frontonasal dysplasia.

Three patients with the osteochondrodysplasia and hypertrichosis syndrome--Cantu syndrome.

Cantu syndrome is a rare condition whose main features are hypertrichosis, cardiac anomalies and wide ribs. Four children have been described and we now present details of a further three. The parents of one of these are first cousins, adding weight to Cantu's theory that the condition is an autosomal recessive disease.

Rapadilino syndrome--a non-Finnish case.

We report on a boy with RAPADILINO syndrome. Including this report seven children with this syndrome have been described. The patient developed a poikilodermatous skin rash, suggesting overlap with the Rothmund-Thompson syndrome.

The autosomal dominant syndrome with congenital stapes ankylosis, broad thumbs and hyperopia.

A family is reported with conductive hearing loss, hyperopia, broad thumbs and broad first toes. The family resembles a previous reported family (Teunissen B, Cremers CWRJ (1990) Laryngoscope 100: 380-384) but additionally all affected members have a typical face. Overlap of the Teunissen and Cremers syndrome with the facio-audio-symphalangism syndrome and proximal symphalangism is discussed.

A syndrome of brachyphalangy, polydactyly and absent tibiae.

We report two unrelated children with a new syndrome consisting of polydactyly and tibial aplasia in the lower limbs. severe brachyphalangy in the hands, malformed ears and a micropenis.

Selective IgG2 subclass deficiency--a marker for the syndrome of pre/postnatal growth retardation, developmental delay, hypotrophy of distal extremities, dental anomalies and eczema.

We report a third family with members displaying pre- and postnatal growth retardation, hypotonia, psychomotor retardation, small puffy hands and feet, dental anomalies and eczematous skin. The four affected members are all females born to unrelated parents consistent with the previously proposed autosomal recessive mode of inheritance. We report a further clinical feature of selective immunoglobulin IgG2 subclass deficiency which would explain some of the clinical findings and might provide an immunological marker for diagnostic confirmation of the syndrome.

Normal erythrocyte membrane Gs alpha bioactivity in two unrelated patients with acrodysostosis.

Shortening of the tubular bones of the hands and feet with cone shaped epiphyses is known as peripheral dysostosis and is common to several syndromes including acrodysostosis and Albright's hereditary osteodystrophy (AHO). The underlying defect in AHO is known to be a reduction in bioactivity of the alpha subunit of the signal transducing protein, Gs, and heterozygous deactivating mutations have been shown in the Gs alpha gene. Because of additional overlapping clinical and radiological features it has been suggested that acrodysostosis and AHO represent poles of a single diagnostic spectrum. We have measured Gs alpha bioactivity in two unrelated patients with a clinical diagnosis of acrodysostosis and found both to be normal. Mutation analysis of the Gs alpha gene showed no sequence variation in 12 of the 13 exons examined. These results indicate that, at least in a proportion of patients with acrodysostosis, the condition is aetiologically distinct from AHO.

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.

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.

A distinctive overgrowth syndrome with polysyndactyly.

We report a female infant with 3-4 syndactyly of the fingers and postaxial polydactyly of all four limbs. She was large at birth and died at the age of 6 months.

Moebius syndrome, an axonal neuropathy and hypogonadism.

We report the sixth patient with the Moebius syndrome, an axonal peripheral neuropathy and hypogonadism. This is probably an entity separate from the Moebius syndrome.

Hidrotic ectodermal dysplasia of hair, teeth, and nails: case reports and review.

We report two families with the Witkop "tooth and nail syndrome". This term is a misnomer, as the hair was mildly involved in the original case reports and in the families reported here.

Nance-Sweeney chondrodysplasia--a further case?

A 52-year-old male with short stature due to short limbs, a cleft palate and subcutaneous calcification was described by Nance and Sweeney in 1970. His parents were consanguineous and two female sibs and two cousins were said to be similarly affected, thus the authors proposed that this was a previously undescribed recessively inherited chondrodystrophy. We describe a patient with short stature due to short limbs, subcutaneous calcification, and a cleft palate with features similar to those described by Nance and Sweeney.

PEHO or PEHO-like syndrome?

PEHO syndrome is a rare progressive infantile encephalopathy, with variable age of onset of hypotonia, convulsions, mental retardation, oedema, and optic atrophy. Neuroimaging shows cerebellar and brainstem atrophy in most instances. A PEHO-like syndrome has been described in which those affected do not have the typical changes on neuroimaging. We report four new cases, two isolated cases and two sisters, who might be part of the PEHO-like syndrome.

Two brothers with deafness, femoral epiphyseal dysplasia, short stature and developmental delay.

Two brothers whose parents are second cousins have short stature, femoral epiphyseal dysplasia, umbilical and inguinal herniae, sensorineural deafness and developmental delay. Both are facially dysmorphic in that the face is triangular in shape with a pointed chin when viewed from the front.

Three mildly retarded siblings with congenital cataracts, sensorineural deafness, hypogonadism, hypertrichosis and short stature: a new syndrome?

We report three male siblings with mild mental retardation, congenital cataract, sensorineural deafness, hypogonadism, hypertrichosis and short stature. This combination has not been previously reported and we suggest this is a new syndrome. Although X-linked recessive inheritance cannot be fully excluded, we favour autosomal recessive inheritance because of parental consanguinity.

Detection of hemizygosity at the elastin locus by FISH analysis as a diagnostic test in both classical and atypical cases of Williams syndrome.

A small pilot study has been carried out in order to assess the reliability of the detection of hemizygosity at the elastin locus by fluorescence in situ hybridisation (FISH) analysis, as a diagnostic test in both classical and atypical cases of Williams syndrome (WS). Five subjects with WS and five others in whom a diagnosis could not be confirmed on clinical criteria alone were evaluated. Hemizygosity at the elastin locus by FISH analysis was detected in all classical Williams syndrome cases and in three of the five atypical subjects. Furthermore, a combination of a few specific facial features found to be present in all subjects with the elastin gene hemizygosity has been suggested to aid the index of clinical suspicion.