Search

Background: Goltz-Gorlin syndrome or focal dermal hypoplasia is a highly variable, X-linked dominant syndrome with abnormalities of ectodermal and mesodermal origin. In 2007, mutations in the PORCN gene were found to be causative in Goltz-Gorlin syndrome.Method: A series of 17 patients with Goltz-Gorlin syndrome is reported on, and their phenotype and genotype are described.Results: In 14 patients (13 females and one male), a PORCN mutation was found. Mutations included nonsense (n = 5), frameshift (n = 2), aberrant splicing (n = 2) and missense (n = 5) mutations. No genotype-phenotype correlation was found. All patients with the classical features of the syndrome had a detectable mutation. In three females with atypical signs, no mutation was found. The male patient had classical features and showed mosaicism for a PORCN nonsense mutation in fibroblasts. Two affected sisters had a mutation not detectable in their parents, supporting germline mosaicism. Their father had undergone radiation for testicular cancer in the past. Two classically affected females had three severely affected female fetuses which all had midline thoracic and abdominal wall defects, resembling the pentalogy of Cantrell and the limb-body wall complex. Thoracic and abdominal wall defects were also present in two surviving patients. PORCN mutations can possibly cause pentalogy of Cantrell and limb-body wall complexes as well. Therefore, particularly in cases with limb defects, it seems useful to search for these.Conclusions: PORCN mutations can be found in all classically affected cases of Goltz-Gorlin syndrome, including males. Somatic and germline mosaicism occur. There is no evident genotype-phenotype correlation.

We have recently shown that Okihiro syndrome results from mutation in the putative zinc finger transcription factor gene SALL4 on chromosome 20q13.13-13.2. There is considerable overlap of clinical features of Okihiro syndrome with other conditions, most notably Holt-Oram syndrome, a condition in part resulting from mutation of the TBX5 locus, as well as acro-renal-ocular syndrome. We analysed further families/patients with the clinical diagnosis of Holt-Oram syndrome and acro-renal-ocular syndrome for SALL4 mutations. We identified a novel SALL4 mutation in one family where the father was originally thought to have thalidomide embryopathy and had a daughter with a similar phenotype. We also found two novel mutations in two German families originally diagnosed as Holt-Oram syndrome and a further mutation in one out of two families carrying the diagnosis acro-renal-ocular syndrome. Our results show that some cases of "thalidomide embryopathy" might be the result of SALL4 mutations, resulting in an increased risk for similarly affected offspring. Furthermore we confirm the overlap of acro-renal-ocular syndrome with Okihiro syndrome at the molecular level and expand the phenotype of SALL4 mutations.

Fraser syndrome is characterised by cryptophthalmos, cutaneous syndactyly, malformations of the larynx and genitourinary tract, craniofacial dysmorphism, orofacial clefting, mental retardation, and musculoskeletal anomalies. The inheritance is autosomal recessive. No diagnostic cytogenetic abnormalities have been documented in affected patients, and no molecular genetic studies have been reported. We have reviewed 117 cases diagnosed as Fraser syndrome or cryptophthalmos published since the comprehensive review of Thomas et al in 1986 in order to validate the published diagnostic criteria and to delineate the phenotype associated with this syndrome. Our series showed more females (57/117) than males and consanguinity was present in 29/119 (24.8%). Eighty-eight patients satisfied the diagnostic criteria for Fraser syndrome (75%). Cryptophthalmos was present in 103/117 (88%), syndactyly in 72/117 (61.5%), and ambiguous genitalia in 20/117 (17.1%). Ear malformations were recorded in 69/117 (59%), and renal agenesis in 53/117 (45.3%). Use of the published diagnostic criteria excluded several patients with cryptophthalmos and one or more physical feature(s) consistent with Fraser syndrome. The frequency of additional anomalies in our series was also higher than previously reported (for example, imperforate anus or anal stenosis were found in 34/117 (29%) compared with 2/124 (2%) in the series of Thomas et al (1986) and choanal stenosis or atresia was present in 7/117 (6%) compared to 0/124. These findings emphasise the clinical variability associated with Fraser syndrome and support genetic heterogeneity of the syndrome. We also noted patterns of anomalies (for example, bicornuate uterus with imperforate anus or anal stenosis and renal malformations) that are found in other syndromes and associations without cryptophthalmos, suggesting that common modifier genes may explain some of the phenotypic variation in Fraser syndrome.

The acrofacial dysostoses (AFD) are a heterogeneous group of disorders characterised by defects in craniofacial and limb development. The hallmarks include downward slanting palpebral fissures, malar hypoplasia, and receding chin (retrognathia) combined with variable limb malformations. The predominantly preaxial form is called Nager AFD and the predominantly postaxial form is called Genee-Wiedeman or Miller syndrome.1 A translocation t(X;9) suggests the localisation of a gene for Nager AFD on chromosome 9q32.2 More distally, on 9q34, one of the two major genes for tuberous sclerosis ( TSC1 ) is located. Tuberous sclerosis (TSC) is an autosomal dominant trait with variable expression most frequently characterised by neurological impairment (seizures and learning difficulties), by dermatological manifestations (facial angiofibromas, periungual fibromas, shagreen patches, and hypopigmented macules), and by renal manifestations including angiomyolipomas and cystic disease.3 The second gene for TSC, TSC2 , maps to chromosome 16p13.3 tail to tail with the major gene for autosomal dominant polycystic kidney disease (ADPKD), the PKD1 gene. These genes are separated by 63 bp.4 The main symptom of ADPKD is the occurrence of a large number of fluid filled cysts in the kidneys. Cysts can in general be detected by ultrasonography or CT scanning around the second or third decade of life and end stage renal failure occurs at a mean age of 53 years in PKD1 patients.5 ADPKD is a systemic disorder with possible extrarenal manifestations such as cysts in other organs (particularly the liver), hypertension, cardiac valve abnormalities, and cerebral aneurysms. Features of TSC and ADPKD have been observed in patients with a TSC2-PKD1 contiguous gene syndrome. In these patients, a large portion of the adjacent TSC2 and PKD1 genes has been deleted on one chromosome. In a study by Sampson et al ,6 17 of 22 patients with such a deletion were …

An unreported missense mutation of the ribosomal S6 kinase 2 (RSK2) gene has been identified in two male sibs with a mild form of Coffin-Lowry syndrome (CLS) inherited from their healthy mother. They exhibit transient severe hypotonia, macrocephaly, delay in closure of the fontanelles, normal gait, and mild mental retardation, associated in the first sib with transient autistic behaviour. Some dysmorphic features of CLS (in particular forearm fullness and tapering fingers) and many atypical findings (some of which were reminiscent of FG syndrome) were observed as well. The moderate phenotypic expression of this mutation extends the CLS phenotype to include less severe mental retardation and minor, hitherto unreported signs. The missense mutation identified may be less deleterious than those previously described. As this mutation occurs in a protein domain with no predicted function, it could be responsible for a conformational change affecting the protein catalytic function, since a non-polar amino acid is replaced by a charged residue. Keywords: Coffin-Lowry syndrome; RSK2

Holt-Oram syndrome is an autosomal dominant disorder characterised by radial ray and congenital heart defects. Recently, a gene for this disorder has been identified on chromosome 12q24.1, encoding a T box transcription factor. However, the functional role of the gene product is not completely understood. We present results of neurological, radiological, and muscle magnetic resonance imaging (MRI) investigations in 13 patients from eight unrelated families. Besides heart defects, clinical signs ranged from thenar abnormalities to bilateral phocomelia. The former were present in all patients. MRI showed hypoplasia of discrete muscles which clinically showed as non-progressive weakness. The structural pattern of residual muscles was normal on MRI, which together with normal muscular power, electromyography, and muscle enzyme investigations excluded a progressive neuromuscular disorder. The number and location of hypoplastic muscles correlated with the severity of skeletal involvement. Thus, patients with hypoplasia of large and proximal muscles had phocomelia, and those with mere intrinsic hand muscle hypoplasia had only a triphalangeal thumb or no skeletal malformation. On the basis of these observations, we conclude that disturbed fetal limb muscle development is involved in the bony malformations of the upper limbs.

A clinical and genetic study of the Holt-Oram syndrome (HOS) has been carried out in the United Kingdom involving 55 cases designated Holt-Oram syndrome, together with their parents and sibs. Data from the clinical assessment of both familial and isolated cases were used to define the HOS phenotype and to outline the spectrum of abnormalities, especially factors affecting severity. Skeletal defects affected the upper limbs exclusively and were bilateral and asymmetrical. They ranged from minor signs such as clinodactyly, limited supination, and sloping shoulders to severe reduction deformities of the upper arm (4.5%). The radial ray was predominantly affected than the right. All affected cases showed evidence of upper limb involvement. Cardiac defects were seen in 95% of familial cases and included both atrial septal defect (ASD, 34%) and ventricular septal defect (VSD, 25%); 39% had only ECG changes. Cardiac involvement ranged from asymptomatic conduction disturbances to multiple structural defects requiring surgery in infancy. Sudden death could be caused by heart block. Inheritance was autosomal dominant with 100% penetrance and no evidence of reduced fitness. Increasing severity occurred in succeeding generations consistent with anticipation.

Absence or hypoplasia of the tibia has been reported to occur as an isolated hereditary malformation as well as a feature of several autosomal recessive and autosomal dominant syndromes. We report three sibs with absence or hypoplasia of the tibia in association with other malformations whose parents are first cousins once removed. These infants appear to have a "new" autosomal recessive syndrome.

Background The lethal short rib polydactyly syndromes (SRP type I-IV) are characterised by notably short ribs, short limbs, polydactyly, multiple anomalies of major organs, and autosomal recessive mode of inheritance. Among them, SRP type II (Majewski; MIM 263520) is characterised by short ovoid tibiae or tibial agenesis and is radiographically closely related to SRP type IV (Beemer-Langer; MIM 269860) which is distinguished by bowed radii and ulnae and relatively well tubulated tibiae. NEK1 mutations have been recently identified in SRP type II. Double heterozygosity for mutations in both NEK1 and DYNC2H1 in one SRP type II case supported possible digenic diallelic inheritance. Methods The aim of this study was to screen DYNC2H1 and NEK1 in 13 SRP type II cases and seven SRP type IV cases. It was not possible to screen DYNC2H1 in two patients due to insufficient amount of DNA. Results The study identified homozygous NEK1 mutations in 5/13 SRP type II and compound heterozygous DYNC2H1 mutations in 4/12 cases. Finally, NEK1 and DYNC2H1 were excluded in 3/12 SRP type II and in all SRP type IV cases. The main difference between the mutation positive SRP type II group and the mutation negative SRP type II group was the presence of holoprosencephaly and polymycrogyria in the mutation negative group. Conclusion This study confirms that NEK1 is one gene causing SRP type II but also reports mutations in DYNC2H1, expanding the phenotypic spectrum of DYNC2H1 mutations. The exclusion of NEK1 and DYNC2H1 in 3/12 SRP type II and in all SRP type IV cases further support genetic heterogeneity.

Triphalangeal thumb (TPT), a long, finger-like thumb with three phalanges instead of two, is regarded as a subtype of preaxial polydactyly. It can occur as a sporadic disorder, but is more often seen as a dominant familial trait. We describe four white Dutch families in which triphalangeal thumb has variable expression and is sometimes associated with preaxial extra rays, rudimentary postaxial polydactyly, cutaneous syndactyly of the hands, and, rarely, postaxial polydactyly and syndactyly of the feet. A comparison with similar familial conditions reported during the past 10 years is provided. The potential significance of linkage and molecular genetic analysis for better insight into the pathogenesis of complex hand malformations is discussed.

We report two new unrelated infants with short rib-polydactyly syndrome (SRPS) whose clinical and radiological features overlap the four established forms of lethal SRPS, so that it is difficult to classify them into any one particular type. One of the babies had one of the most radiologically severe SRPS ever published. The patients presented here support the previously reported hypothesis that this group of disorders might be a continuous spectrum rather than separate entities.

Preaxial polydactyly was observed in up to five generations of an Indian family living in a village in the Rajkot district (Gujarat). Among the 71 affected members, 45 were males and 26 were females. All these affected members showed preaxial polydactyly manifesting as a well formed, articulated extra digit of the hand or foot. Twenty other cases were also identified with polydactyly involving triphalangeal digits replacing the thumbs or duplication of the big toe(s). To the best of our knowledge, the present family is the largest in which several members have preaxial polydactyly of different types. No other abnormalities were apparent. The present study strongly suggests that preaxial polydactyly with a well formed extra digit, triphalangeal thumbs, and duplication of the big toe can be manifestations of the same autosomal dominant gene. It is likely that other factors are modifying the expression of this gene.

Apert syndrome, characterised by craniosynostosis, craniofacial anomalies, and symmetrical syndactyly of the digits (cutaneous and bony fusion), has been associated with two canonical mutations in the FGFR2 gene (S252W, P253R) in the great majority of cases. Since these two alterations have been observed exclusively among these patients, it has been suggested that the S252W and P253R changes may play an important role in the occurrence of syndactyly. In order to verify whether the mutations S252W and P253R could also cause a milder phenotype, without involvement of the limbs, we have screened 22 patients with clinical characteristics compatible with Crouzon or Pfeiffer syndrome for these two particular changes. Surprisingly, we identified a Pfeiffer-like patient with the mutation S252W, and therefore we have shown for the first time the occurrence of one of the canonical Apert mutations without severe abnormalities of the upper and lower extremities.

Maternal diabetes has an established aetiological link with developmental abnormalities, and the prevalence of major congenital malformations in the offspring of affected women is approximately 4-8%, compared to the general population risk of about 3%. Hallucal polydactyly, particularly with an unusual proximal placement of the extra digit, has been reported as a distinctive anomaly in diabetic embryopathy. We report on a child of a diabetic mother with this unusual form of hallucal polydactyly, together with other skeletal anomalies, confirming that this malformation is a useful clinical marker for the diagnosis of diabetic embryopathy.

We describe a family with autosomal dominant inheritance of anal anomalies, renal tract abnormalities, genital malformations, and syndactyly. These clinical manifestations do not clearly fall into any previously described syndrome. A mother and daughter had almost identical congenital malformations, short stature, and unusual facies. The proband was born with anal stenosis, a rectovaginal fistula, clitoral hypertrophy, a pelvic right kidney, and syndactyly of both feet. Her daughter had the same anal, clitoral, and foot anomalies, a solitary pelvic kidney, and no fistula. This family is likely to represent autosomal dominant inheritance of a new combination of malformations, which may overlap with the Townes-Brocks syndrome, but does not fall into a current diagnostic category.

We report a girl with mirror hands and feet and associated groove of the nasal columella. She represents only the sixth reported case of this spectrum of congenital anomalies,first reported by Laurin and Sandrow.

Nail patella syndrome (NPS) is an autosomal dominant condition affecting the nails, skeletal system, kidneys, and eyes. Skeletal features include absent or hypoplastic patellae, patella dislocations, elbow abnormalities, talipes, and iliac horns on x ray. Kidney involvement may lead to renal failure and there is also a risk of glaucoma. There is marked inter- and intrafamilial variability. The results of a British study involving 123 NPS patients are compared with previously published studies and it is suggested that neurological and vasomotor symptoms are also part of the NPS phenotype. In addition, the first data on the incidence of glaucoma and gastrointestinal (GI) symptoms in NPS are presented. NPS is caused by loss of function mutations in the transcription factor LMX1B at 9q34. The expansion of the clinical phenotype is supported by the role of LMX1B during development.

A 28 month old girl with dysmorphic features was found to have an interstitial deletion of the short arm of chromosome 7p15.3-7p21.2. The patient had ptosis, dacryostenosis, pectus excavatum, short hands, and her development was normal or mildly delayed. Craniosynostosis and growth retardation, which were present in two other patients with similar deletions, were not present. Because of the mild manifestations, this case expands the clinical spectrum of the 7p15-7p21 deletion phenotype.

Acrocallosal syndrome is an autosomal recessive form of polysyndactyly associated with mental retardation and agenesis of the corpus callosum. There have been suggestions that it is allelic to the Greig cephalopolysyndactyly syndrome. Linkage analysis, using flanking markers, shows this suggestion is unlikely to be correct.

We report on the occurrence of coronal craniosynostosis, anal anomalies, and porokeratosis in two male sibs. A third male sib was phenotypically normal as were the parents. The occurrence of these three clinical features has, to our knowledge, not been reported before. Cutaneous or anal anomalies or both have been reported in a number of syndromes associated with craniosynostosis, including Crouzon, Pfeiffer, Apert, and Beare-Stevenson syndromes. These syndromes are associated with mutations in the fibroblast growth factor receptor genes FGFR1, FGFR2, and FGFR3. They are inherited in an autosomal dominant fashion. In contrast, the cases we report do not carry any of the common FGFR mutations and the pedigree suggests autosomal or X linked recessive inheritance.

Pfeiffer-type cardiocranial syndrome is a rare condition reported previously in three patients, two of whom were sibs. All three patients shared features that included growth and developmental retardation, sagittal synostosis, hypertelorism, low set ears, micrognathia with mandibular ankylosis, congenital heart defects, and genital anomalies. The purposes of this report are to present a fourth patient with features of the Pfeiffer-type cardiocranial syndrome, to expand the clinical phenotype of this condition, and to present evidence that supports the concept that this phenotype represents a distinct nosological entity.

We report an atypical case of the Poland anomaly. Unreported features are that the hand abnormality is on the contralateral side to the chest wall defect, there is an ulnar ray predominance, and lack of syndactyly.

We present a female patient with acrocephalopolysyndactyly, pentalogy of Fallot, psychomotor retardation, and hypoacusis with a de novo, apparently balanced, reciprocal translocation 46,XX,t(1;18)(p31;q11).

We report on a patient with humeroradioulnar synostosis and lambdoid synostosis. The case differs from three previously described cases in minor details, but the upper limb abnormalities are strikingly similar.

A form of thoracic and pelvic dysostosis is reported in a mother and her son. The short ribs caused respiratory distress in the baby and raised the possibility of asphyxiating thoracic dystrophy (ATD). The radiological features, however, distinguish this benign condition from ATD and other described skeletal dysplasias.

An alpha-L-iduronidase deficiency syndrome has been described in adult male twins, which was phenotypically distinct from that of the Hurler and Scheie syndromes or the chondroitinsulphaturias. Multiple dysostosis and stiff joints were present without cloudy corneae, cardiac involvement and mental or physical retardation. This clinical phenotype appeared to be a newly recognized allelic mutation at the iduronidase locus but does not exclude a non-allelic mutation coding for a subunit of the iduronidase molecule.

A syndrome characterised by asymmetrical radial dysplasia, dysmorphic facies, conductive deafness, and external ear deformity is described in a mother and her daughter. This combination of anomalies has previously been reported in members of a single family. The disorder appears to be clinically and genetically distinct from others associated with radial dysplasia, such as Nager's acrofacial dysostosis and the lachrimoauriculoradiodental syndrome. Inheritance is autosomal dominant, with marked variation in expression of the mutant gene.

A boy with intrauterine growth retardation, microcephaly, dysostosis of the skull, hypoplastic facial bones, labiogingival retraction, agenesis of the clavicles, distal aphalangia, and severely hypoplastic thumbs and halluces is described. The features are consistent with the Yunis-Varon syndrome. Review of published reports shows this to be a generalised disorder with variable manifestations in the skeletal, ectodermal, and cardiovascular systems. The consanguinity of the parents of the present case is in agreement with autosomal recessive inheritance.

We report a six year old male with mental retardation, postaxial polydactyly and syndactyly, atrichia congenita totalis, severe seborrhoeic dermatitis, recurrent staphylococcal skin sepsis, and Perthes' disease of the hip. His birth may have resulted from an incestuous mating.

We present a four year old boy with short stature, disproportionate microcephaly, developmental delay, convulsions, bilateral cleft lip and palate, and bifid right thumb.

A female infant is described with a lethal short rib syndrome, similar to a form of short rib-polydactyly syndrome but without polydactyly. It is felt that this infant has the same condition as that described by Beemer et al.