Bilateral hereditary micro-epiphyseal dysplasia: further delineation of the phenotype with 40 years follow-up.

Bilateral hereditary micro-epiphyseal dysplasia (BHMED) is a distinct skeletal dysplasia with specific clinical and radiological findings. It was first published in 1959. We have re-examined the original family for further delineation of the phenotype.

Molecular analysis of SALL1 mutations in Townes-Brocks syndrome.

Townes-Brocks syndrome (TBS) is an autosomal dominantly inherited malformation syndrome characterized by anal, renal, limb, and ear anomalies. Recently, we showed that mutations in the putative zinc finger transcription factor gene SALL1 cause TBS. To determine the spectrum of SALL1 mutations and to investigate the genotype-phenotype correlations in TBS, we examined 23 additional families with TBS or similar phenotypes for SALL1 mutations. In 9 of these families mutations were identified. None of the mutations has previously been described. Two of these mutations are nonsense mutations, one of which occurred in three unrelated families. Five of the mutations are short deletions. All of the mutations are located 5' of the first double zinc finger (DZF) encoding region and are therefore predicted to result in putative prematurely terminated proteins lacking all DZF domains. This suggests that only SALL1 mutations that remove the DZF domains result in TBS. We also present evidence that in rare cases SALL1 mutations can lead to phenotypes similar to Goldenhar syndrome. However, phenotypic differences in TBS do not seem to depend on the site of mutation.

Uniparental disomy with and without confined placental mosaicism: a model for trisomic zygote rescue.

In the population of children born after prenatal cytogenetic investigation in chorionic villi at our department from 1992 to 1995 (N = 3940), three are known to us with uniparental disomy. One case of maternal heterodisomy 16 was prenatally discovered because of trisomy 16 in direct chorionic villi with subsequently normal amniotic fluid cells. The other two had normal karyotypes in chorionic villi. Maternal heterodisomy 15 was postnatally detected in one of them because of Prader-Willi syndrome. Maternal hetero/isodisomy 16 was accidentally encountered in the other case in the course of prenatal DNA analysis of the tuberous sclerosis complex 2 region at 16p13.3. A model is presented for the understanding of the various combinations of karyotypes in direct chorionic villi, cultured chorionic villi and the fetus in the case of successful and unsuccessful trisomic zygote rescue.

Restrictive dermopathy. Report of 12 cases. Dutch Task Force on Genodermatology.

BACKGROUND: This study describes 12 cases of restrictive dermopathy seen during a period of 8 years by the Dutch Task Force on Genodermatology. We present these unique consecutive cases to provide more insight into the clinical picture and pathogenesis of the disease. OBSERVATIONS: Clinical features in more than 85% of these children were prematurity, fixed facial expression, micrognathia, mouth in O position, rigid and tense skin with erosions and denudations, and multiple joint contractures. Ten patients underwent histopathologic skin biopsy. The biopsy results showed flattening of rete ridges in all 10 patients, a thin dermis with collagen aligned parallel to the epidermis in 9 patients, and poorly developed dermal appendages in 9 patients. Additional findings in individual patients included blepharophimosis, inguinal skin tear, skin tear in the frontal neck area that developed during delivery, absent eyelashes, a wide ascendent aorta, and dextrocardia. Fibroblast cultures taken from 5 patients did not show abnormal alpha 2 beta 1 and alpha 1 beta 1 integrin expressions. CONCLUSIONS: The alleged rarity of restrictive dermopathy may be partially caused by medical unfamiliarity with this entity, despite its characteristic clinical and histopathologic picture. The pathogenesis of the disease still needs to be elucidated.

A gene for nonspecific X-linked mental retardation (MRX41) is located in the distal segment of Xq28.

We report on a family in which nonsyndromal mild to moderate mental retardation segregates as an X-linked trait (MRX41). Two point linkage analysis demonstrated linkage between the disorder and marker DXS3 in Xq21.33 with a lod score of 2.56 at theta = 0.0 and marker DXS1108 in Xq28 with a lod score of 3.82 at theta = 0.0. Multipoint linkage analysis showed that the odds for a location of the gene in Xq28 vs Xq21.33 are 100:1. This is the fourth family with non-specific X-linked mental retardation with Xq28-qter as the most likely gene localization.

Analysis of a large family with the second type of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disorder A mutation in at least three different genes can cause the disease. A mutation in the first gene, the PKD1 gene, which has been identified on chromosome 16p13.3, accounts for ADPKD in approximately 86% of the families with this disorder. In the majority of the other ADPKD families the disease is caused by a mutation in a second gene, the PKD2 gene. This gene has been mapped to chromosome 4q21-22, but has not yet been identified. In a few families ADPKD is not caused by a mutation in either the PKD1 or the PKD2 gene. The locus for a possible third gene has not yet been determined. Now that haplotype analysis with polymorphic markers at the ADPKD1 and ADPKD2 loci is possible, we can easily distinguish between both forms of ADPKD. We describe a large Dutch family in which ADPKD is linked to chromosome 4. Compared with ADPKD1 families, the disease in this family tends to run a milder course, as has been described previously for other ADPKD2 families.

DNA diagnosis of Prader-Willi and Angelman syndromes with the probe PW71 (D15S63).

Previously, 158 nuclear families with probands suspected of having either Prader Willi (PWS) or Angelman syndrome (AS) were analyzed with polymorphic DNA markers from the 15q11-13 region. These cases have been re-evaluated with the probe PW71 (D15S63), which detects parent-of-origin-specific alleles after digestion with a methylation-sensitive restriction enzyme (HpaII). Application of PW71 to DNA samples isolated from leucocytes, confirmed the deletions and uniparental disomies detected earlier by marker analysis, and resolved 50% of the previously uninformative (n = 18) cases. PW71 and restriction fragment length polymorphism analysis indicated that, in all resolved cases, disomies of the 15q11-13 region were present. The use of PW71 increased the percentage of disomies detected in our PWS and AS patient groups. Almost 50% of our PWS patients and 17% of the AS patients showed a disomy of maternal or paternal origin, respectively. DNA of first trimester chorionic villi and of fibroblast cultures was not suitable for analysis with PW71 because of different methylation patterns. The application of PW71 is recommended for the diagnosis of the PWS and AS, with respect to DNA samples from blood.

Clinical and molecular studies in fragile X patients with a Prader-Willi-like phenotype.

A special subphenotype of the fragile X syndrome is reported which is characterised by extreme obesity with a full, round face, small, broad hands/feet, and regional skin hyperpigmentation. It resembles the Prader-Willi syndrome (PWS) and might therefore be named 'Prader-Willi-like'. Unlike the PWS, these PW-like fragile X patients lack the neonatal hypotonia with feeding problems during infancy followed by hyperphagia from toddlerhood. We describe five new fragile X patients and present a clinical update of three previously described patients with the PW-like phenotype. In one family, segregation of either the classical Martin-Bell or the PW-like phenotype was observed and in another family there was repeated transmission of the PW-like phenotype. Previously, one of the patients had been misdiagnosed as having classical PWS, based on clinical findings. Molecular studies of the FMR-1 gene showed the typical full mutations as seen in fragile X syndrome males. Molecular analysis of the 15q11-13 region, which is deleted in the majority of classical PWS patients, did not show any detectable abnormalities. In a group of 26 patients with suspected Prader-Willi syndrome but without detectable molecular abnormalities of chromosome 15, one fragile X patient was found. These clinical and molecular findings illustrate the necessity to perform DNA analysis of the FMR-1 gene in mentally retarded patients presenting with a PW phenotype but without the PWS specific cytogenetic/molecular abnormalities of chromosome 15.

Avoidance of emergency surgery in newborn infants with trisomy 18.

Trisomy 18 (Edwards' syndrome) presents with characteristic external features as well as life-threatening abnormalities; many of these abnormalities require surgical correction during the neonatal period. Children with trisomy 18 have a very short life expectancy, and all long-term survivors have severe mental retardation. Difficult medical and ethical issues arise over whether or not to institute treatment when a newborn infant with suspected trisomy 18 has a life-threatening anomaly. We studied the policy of treatment in seven patients with clinical Edwards' syndrome. For three, the period of uncertainty was shortened because trisomy 18 was rapidly diagnosed by karyotyping of a bone-marrow aspirate. Four of the patients underwent surgery before the diagnosis of trisomy 18 was confirmed by routine karyotyping in lymphocytes; karyotyping in bone marrow might have allowed invasive treatment to be avoided in three of these. Rapid confirmation of clinically suspected Edwards' syndrome is very important because surgery may then be withheld. A newborn infant with trisomy 18 should be considered as a patient with a hopeless outlook who ought not to be subjected to invasive procedures. The decision to withdraw or withhold treatment should be discussed frankly with the parents. The period of uncertainty can be reduced to a minimum by the use of karyotyping in bone marrow.

Molecular detection of a translocation (Y;11) (q11.2;q24) in a 45,X male with signs of Jacobsen syndrome.

A 45,X karyotype was found in a boy with dysmorphic features, hypoglycaemia and pancytopenia. DNA analysis showed the presence of the Y-chromosomal DNA sequences SRY, ZFY, DYZ4, DYZ3 and DYS1. Using fluorescent in situ hybridization, we located DYZ4 and DYZ3 on chromosome 11qter and concluded that a de novo translocation (Y;11) (q11.2;q24) with a deletion of 11q24----qter and a deletion of Yq11.2----Yqter were present; Jacobsen syndrome and azoospermia are associated with these deletions. Signs of Jacobsen syndrome were observed in the patient.

Isolated lissencephaly sequence associated with a microdeletion at chromosome 17p13.

DNA markers YNZ22.1, YNH37.3, 144D6 and VAW508 were studied in a patient with the isolated lissencephaly sequence (ILS). A normal karyotype was found in the patient. The DNA of the patient showed deletions of markers YNZ22.1 and YNH37.3. This is the first report of a case of ILS (with grade 3 lissencephaly) with a submicroscopic deletion. The presence of a microdeletion in 17p13 in an ILS patient indicates that Miller-Dieker syndrome and ILS have a common etiology.

The mutation delta F508 on Dutch cystic fibrosis chromosomes: frequency and relation to patients age at diagnosis.

We tested 190 chromosomes from Dutch cystic fibrosis (CF) patients and carriers for the presence or absence of the major CF mutation delta F508. This mutation was found on 77% of the Dutch CF chromosomes. We observed a significant difference in the distribution of the ages at diagnosis between homozygotes for delta F508 and the other patients. delta F508 homozygotes tend to be identified as patients at neonatal or infantile age. The age at diagnosis of patients with at least one unknown allele, on the other hand, ranged between neonatal and young adult age.