Bone involvement and mineral metabolism in Williams' syndrome.

CONTEXT: The previous studies suggested a possible increased risk of hypercalcaemia and reduced bone mineral density (BMD) in Williams' syndrome (WS). However, an extensive study regarding bone metabolism has never been performed. OBJECTIVE: To investigate bone health in young adults with WS. DESIGN: Cross-sectional study. SETTINGS: Endocrinology and Metabolic Diseases and Medical Genetic Units. PATIENTS: 29 WS young adults and 29 age- and sex-matched controls. MAIN OUTCOME MEASURES: In all subjects, calcium, phosphorus, bone alkaline phosphatase (bALP), parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHVitD), osteocalcin (OC), carboxyterminal cross-linking telopeptide of type I collagen (CTX), 24-h urinary calcium and phosphorus, femoral-neck (FN) and lumbar-spine (LS) BMD and vertebral fractures (VFx) were assessed. In 19 patients, serum fibroblast growth factor-23 (FGF23) levels were measured. RESULTS: WS patients showed lower phosphorus (3.1 ± 0.7 vs 3.8 ± 0.5 mg/dL, p = 0.0001) and TmP/GFR (0.81 ± 0.32 vs 1.06 ± 0.25 mmol/L, p = 0.001), and an increased prevalence (p = 0.005) of hypophosphoremia (34.5 vs 3.4%) and reduced TmP/GFR (37.9 vs 3.4%). Moreover, bALP (26.3 ± 8.5 vs 35.0 ± 8.0 U/L), PTH (24.5 ± 12.6 vs 33.7 ± 10.8 pg/mL), OC (19.4 ± 5.3 vs 24.5 ± 8.7 ng/mL), and FN-BMD (- 0.51 ± 0.32 vs 0.36 ± 0.32) were significantly lower (p < 0.05), while CTX significantly higher (401.2 ± 169.3 vs 322.3 ± 122.4 pg/mL, p < 0.05). Serum and urinary calcium and 25OHVitD levels, LS-BMD and VFx prevalence were comparable. No cases of hypercalcemia and suppressed FGF23 were documented. Patients with low vs normal phosphorus and low vs normal TmP/GFR showed comparable FGF23 levels. FGF23 did not correlate with phosphorus and TmP/GFR values. CONCLUSIONS: Adult WS patients have reduced TmP/GFR, inappropriately normal FGF23 levels and an uncoupled bone turnover with low femoral BMD.

Phenotype of five cases of prenatally diagnosed campomelic dysplasia harboring novel mutations of the SOX9 gene.

OBJECTIVES: Campomelic dysplasia is a rare congenital skeletal disorder characterized by bowing of the long bones and a variety of other skeletal and extraskeletal defects, many of which can now be identified prenatally using advanced ultrasound equipment. The disorder is caused by mutations in SRY-box 9 (SOX9), a gene that is abundantly expressed in chondrocytes as well as in other tissues. However, the correlation between genotype and phenotype is still unclear. We report five cases of prenatally detected campomelic dysplasia in which the diagnosis was confirmed by molecular analysis. METHODS: Ultrasound examinations were performed between 12 and 32 weeks. Standard fetal biometric measurements were obtained. Fetal sex was determined sonographically and confirmed by chromosomal analysis. Genomic DNA was obtained in four cases before termination of pregnancy from chorionic villi or amniocytes and in one case postnatally from peripheral blood. RESULTS: Skeletal dysplasia, most often limb shortening and bowed femora, was observed in one case in the first trimester, in three cases in the second trimester and in one case, presenting late for antenatal care, in the third trimester. Four of the pregnancies were terminated and one was carried to term. Postmortem/postnatal physical and radiographic examinations confirmed the presence of anomalies characteristic of campomelic dysplasia. A de novo mutation in the SOX9 gene was detected in all four cases that underwent termination. The father of the proband in the case that went to term was a carrier of a somatic mosaic mutation without clinical or radiographic signs of campomelic dysplasia. CONCLUSIONS: It is likely that the integrated expertise of ultrasonographers, obstetricians, pediatricians and clinical geneticists will markedly improve the likelihood of accurate prenatal clinical diagnoses of campomelic dysplasia. This will, in turn, encourage more specific molecular testing and facilitate comprehensive genetic counseling.

Cryptic deletions are a common finding in "balanced" reciprocal and complex chromosome rearrangements: a study of 59 patients.

Using array comparative genome hybridisation (CGH) 41 de novo reciprocal translocations and 18 de novo complex chromosome rearrangements (CCRs) were screened. All cases had been interpreted as "balanced" by conventional cytogenetics. In all, 27 cases of reciprocal translocations were detected in patients with an abnormal phenotype, and after array CGH analysis, 11 were found to be unbalanced. Thus 40% (11 of 27) of patients with a "chromosomal phenotype" and an apparently balanced translocation were in fact unbalanced, and 18% (5 of 27) of the reciprocal translocations were instead complex rearrangements with >3 breakpoints. Fourteen fetuses with de novo, apparently balanced translocations, all but two with normal ultrasound findings, were also analysed and all were found to be normal using array CGH. Thirteen CCRs were detected in patients with abnormal phenotypes, two in women who had experienced repeated spontaneous abortions and three in fetuses. Sixteen patients were found to have unbalanced mutations, with up to 4 deletions. These results suggest that genome-wide array CGH may be advisable in all carriers of "balanced" CCRs. The parental origin of the deletions was investigated in 5 reciprocal translocations and 11 CCRs; all were found to be paternal. Using customized platforms in seven cases of CCRs, the deletion breakpoints were narrowed down to regions of a few hundred base pairs in length. No susceptibility motifs were associated with the imbalances. These results show that the phenotypic abnormalities of apparently balanced de novo CCRs are mainly due to cryptic deletions and that spermatogenesis is more prone to generate multiple chaotic chromosome imbalances and reciprocal translocations than oogenesis.

[Rare diseases: the model of Ospedale Maggiore Policlinico IRCCS Mangiagalli Regina Elena]. / Malattie rare: il modello della Fondazione Ospedale Mag- giore Policlinico IRCCS Mangiagalli Regina Elena.

The rare diseases are a group of diseases which diagnosis, treatement and prevention is a relevant problem all over the world. They are defined on the basis of their very low incidence also if this definition is not equal all over the world. The article offers a review of the national and regional legislation on rare diseases and it describes a survey carried out in Fondazione Ospedale Maggiore Policlinico IRCCS Mangiagalli Regina Elena, a research and teaching hospital, about the organization of the network of doctors who care for these patients.

Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders.

The identification of multilocus imprinting disturbances (MLID) appears fundamental to uncover molecular pathways underlying imprinting disorders (IDs) and to complete clinical diagnosis of patients. However, MLID genetic associated mechanisms remain largely unknown. To characterize MLID in Beckwith-Wiedemann (BWS) and Silver-Russell (SRS) syndromes, we profiled by MassARRAY the methylation of 12 imprinted differentially methylated regions (iDMRs) in 21 BWS and 7 SRS patients with chromosome 11p15.5 epimutations. MLID was identified in 50% of BWS and 29% of SRS patients as a maternal hypomethylation syndrome. By next-generation sequencing, we searched for putative MLID-causative mutations in genes involved in methylation establishment/maintenance and found two novel missense mutations possibly causative of MLID: one in NLRP2, affecting ADP binding and protein activity, and one in ZFP42, likely leading to loss of DNA binding specificity. Both variants were paternally inherited. In silico protein modelling allowed to define the functional effect of these mutations. We found that MLID is very frequent in BWS/SRS. In addition, since MLID-BWS patients in our cohort show a peculiar pattern of BWS-associated clinical signs, MLID test could be important for a comprehensive clinical assessment. Finally, we highlighted the possible involvement of ZFP42 variants in MLID development and confirmed NLRP2 as causative locus in BWS-MLID.

Kaufman oculocerebrofacial syndrome in a girl of 15 years.

Kaufman oculocerebrofacial syndrome (KOS) is a rare autosomal recessive disorder characterized by severe mental retardation, microcephaly, long narrow face, ocular anomalies, and long thin hands and feet. To our knowledge only 8 cases have been reported so far, diagnosed at a mean age of 10 years. We report on a girl who was diagnosed at 15 years. Further phenotypic delineation is needed to improve diagnosis of this syndrome early in life.

Cardio-facio-cutaneous (CFC) syndrome: report of an adult without mental retardation.

We report on a 25-year-old woman with typical manifestations of the cardio-facio-cutaneous (CFC) syndrome, but without mental retardation. She had valvular and infundibular pulmonic stenosis, brittle and woolly hair with patchy alopecia, scant body hair, dry and hypohydrotic skin, and characteristic facial traits. To our knowledge, this is the first case of CFC syndrome without mental retardation but typical cutaneous findings.

Variability of the Brachmann-de Lange syndrome.

Brachmann-de Lange syndrome (BDLS) is a relatively common multiple congenital anomaly/mental retardation syndrome, whose cause is unknown. The clinical variability of this condition is well-known. Recently some reports suggested the possible existence of a mild BDLS phenotype. We report on 30 patients in whom a diagnosis of BDLS was made or strongly suspected in 12 different Italian hospitals. Based on clinical evaluation we divided them into two groups, classical and mild BDLS cases. We compare the clinical data of these patients and we discuss the problems which arise in trying to define clear criteria of distinction between these two groups.

"C" trigonocephaly syndrome: clinical variability and possibility of surgical treatment.

We report on 3 new cases of C trigonocephaly syndrome. In addition to the findings characteristic of this condition, one of the patients also had a large omphalocele. This patient was referred from a suburban hospital with a diagnosis of Down syndrome, stressing the fact that C syndrome is still under-recognized and underdiagnosed. Another patient was diagnosed at birth and immediately submitted to craniosynostectomy. A second operation was performed 7 months later resulting in normal brain growth and close to normal psychomotor development at 3 years, in contrast to the third patient, who was not treated surgically and was severely retarded at 4 years.

Limb anomalies following chorionic villus sampling: a registry based case-control study.

Using data from the Italian Multicentric Birth Defect Registry a case-control study was performed to verify if chorionic villus sampling (CVS) was associated with transverse limb defects (TLD), with or without features of oro-mandibular-limb hypogenesis complex (OMLHC), in the exposed offspring. The results show that the risk of TLD and OMLHC is increased following CVS, and is particularly high for CVS performed early in pregnancy, i.e., under 70 days of gestational age. These results, together with a review of other epidemiologic studies, biological data and clinical reports, strongly suggest a causative role of CVS as a risk factor for TLD and indicate that at this stage CVS before 70 days of gestational age should be discouraged as an option for prenatal diagnosis and that all patients wishing to undergo CVS should be informed about the possible risk of the procedure.

X-linked mental retardation with marfanoid habitus: first report of four Italian patients.

We report on 4 new cases of mildly retarded patients with marfanoid habitus and a characteristic constellation of minor anomalies. These patients, although sporadic, are likely to be affected by the same X-linked type of mental retardation described by Lujan et al. (American Journal of Medical Genetics 17:311-322, 1984) and more recently by Fryns and Buttiens (American Journal of Medical Genetics 28:267-274, 1987). The similar psychiatric history in 2 of our patients suggests that psychotic behaviour could be an additional manifestation, previously unrecognized in this condition. Late diagnosis of this relatively new syndrome in all our patients confirms the difficulty of the nosologic definition of mentally retarded individuals on clinical grounds alone. On the other hand, the Lujan-Fryns syndrome appears to be more common than one would have thought.

Seizure and EEG patterns in Angelman's syndrome.

We studied the seizure and polygraphic patterns of 18 patients with Angelman's syndrome. All patients showed movement problems. Eleven patients were also reported to have long-lasting periods of jerky movements. The polygraphic recording showed a myoclonic status epilepticus in nine of them. Seven patients had partial seizures with eye deviation and vomiting, similar to those of childhood occipital epilepsies. These seizures and electroencephalographic patterns suggest that Angelman's syndrome occurs in most of the patients as a nonprogressive, age-dependent myoclonic encephalopathy with a prominent occipital involvement. These findings indicate that, whereas ataxia is a constant symptom in Angelman's syndrome, the occurrence of a transient myoclonic status epilepticus may account for the recurrence of different abnormal movements, namely the jerky ones.

Nasopharyngeal teratoma and diaphragmatic hernia: a non random association?

We describe a female affected by diaphragmatic hernia and nasopharyngeal teratoma. The case is compared with one already reported and possible diagnoses discussed. These cases appear to represent a new syndrome.

[Odontochondrodysplasia]. / L'odontochondrodysplasie.

BACKGROUND: Dentinogenesis imperfecta is exceptionally associated to chondrodysplasia. The aim of this work is to present four cases of such an association. CASE REPORT: These four children (three boys; one girl) suffered from growth retardation, ligamentous hyperlaxity, scoliosis. Main features were present since the first months of life. Dentinogenesis imperfecta was more marked on the first teeth. On X-rays, all patients had short tubular bones, more pronounced at the level of the middle segment of their limbs, with irregular metaphyses. Cone-shaped epiphyses were present on the hands. Iliac wings were square-shaped and vertebral bodies had a posterior wedging. CONCLUSION: These four cases, including two previously published as Goldblatt's syndrome, share the same findings as another case described by this author. We propose the name of odontochondrodysplasia for this apparently unfortuitous association: dentinogenesis imperfecta and chondrodysplasia.

[Syndromes in outpatient experience]. / Le sindromi nell'esperienza ambulatoriale.

We report our experience as clinical geneticists and pediatricians in the management of patients affected by multiple congenital malformations and genetic syndromes. Our aim is to demonstrate that etiological diagnosis, crucial for successful management and counselling, has to be considered the first step in the care of these patients and their families. Coordination of medical interventions, clinical follow-up and psychosocial support have to be included in every out-patient program in this field. Diagnostic approach has to be carried out through a specific methodology which includes extensive clinical expertise in dealing with children affected by multiple congenital anomalies, protocols for major clinical problems, facilities for specific investigations (cytogenetic laboratory, molecular genetics, ecc.), computerized programs for recognising rare syndromes, network of motivated specialists (neurology, ophthalmology, orthopedics, etc.) and possibility of collegial discussion of undiagnosed patients. Psychosocial support and follow-up have to be achieved through trained professionals. Our 5 years of experience in this field (1420 patients) suggest the need for an organized network of services. This could provide the families of children affected by genetic syndromes with a comprehensive management and support program which is lacking in the present health care system.

Amyotrophic lateral sclerosis: a possible example of autosomal recessive inheritance.

A family is reported in which three out of four siblings of a consanguineous healthy couple developed adult onset Amyotrophic Lateral Sclerosis (ALS). All patients showed a similar clinical course with regard to disease progression and absence of cognitive deterioration. Laboratory findings included modification of Spinal Evoked Potential (SEP) and normal value of thiamine and thiamine monophosphate in cerebrospinal fluid (CSF). These data suggest an autosomal recessive mode of inheritance of ASL in this family.