[Surgical therapy of cone-shaped epiphyses of the proximal interphalangeal joints in tricho-rhino-phalangeal syndrome type I: a survey among three successive generations of a single family]. / Chirurgische Therapie der Zapfenepiphysen an den proximalen Interphalangealgelenken beim Tricho-Rhino-Phalangealen Syndrom (TRPS) Typ I: Eine Familenübersicht anhand von drei Generationen.

Report on 6 individuals, occurring in three successive generations of a single family, who were affected by "classical" tricho-rhino-phalangeal syndrome type I. Besides pear-shaped noses, enlarged philtrum, hypotrichosis, premature alopecia, coned epiphysis at the proximal interphaleangeal joints with consecutive ulnar deviation of the long fingers, dysostotic feet, Perthes-like hip dysplasia with multilocated joint laxity and hyposomia were impressing. Height was 168 cm, corresponding to the 50 (th) percentile. Radiographs and 3D-reconstruction of both hands showed asymmetrical brachymetacarpia, brachymesophalangia and painful invaginations of the middle phalanx bases (type 12 according to Giedion). Angular deformities are seen predominantly in the index finger decreasing to the ring finger. Painful cone-shaped epiphyses with ulnar dislocation of the PIP joints were stabilized following resection arthrodesis with tension band osteosynthesis. At reexamination 48 months postoperatively a painfree and powerful pinch grip function of both hands was restored. All family members who showed the phenotypical features of TRPS type I revealed in genetic analysis also identical mutations. Inside the exon 4 in position 1831 there was a nonsens mutation C --> T. Non-afflicted relatives did not show this mutation.

Classic, atypically severe and neonatal Marfan syndrome: twelve mutations and genotype-phenotype correlations in FBN1 exons 24-40.

Mutations in the gene for fibrillin-1 (FBN1) cause Marfan syndrome, an autosomal dominant disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular system. There is a remarkable degree of clinical variability both within and between families with Marfan syndrome as well as in individuals with related disorders of connective tissue caused by FBN1 mutations and collectively termed type-1 fibrillinopathies. The so-called neonatal region in FBN1 exons 24-32 comprises one of the few generally accepted genotype-phenotype correlations described to date. In this work, we report 12 FBN1 mutations identified by temperature-gradient gel electrophoresis screening of exons 24-40 in 127 individuals with Marfan syndrome or related disorders. The data reported here, together with other published reports, document a significant clustering of mutations in exons 24-32. Although all reported mutations associated with neonatal Marfan syndrome and the majority of point mutations associated with atypically severe presentations have been found in exons 24-32, mutations associated with classic Marfan syndrome occur in this region as well. It is not possible to predict whether a given mutation in exons 24-32 will be associated with classic, atypically severe, or neonatal Marfan syndrome.

Genotypic and phenotypic spectrum in tricho-rhino-phalangeal syndrome types I and III.

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities. Three subtypes have been described: TRPS I, caused by mutations in the TRPS1 gene on chromosome 8; TRPS II, a microdeletion syndrome affecting the TRPS1 and EXT1 genes; and TRPS III, a form with severe brachydactyly, due to short metacarpals, and severe short stature, but without exostoses. To investigate whether TRPS III is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, we performed extensive mutation analysis and evaluated the height and degree of brachydactyly in patients with TRPS I or TRPS III. We found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicates that TRPS1 is the major locus for TRPS I and TRPS III. We did not find any mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the five missense mutations alter the GATA DNA-binding zinc finger, and six of the seven unrelated patients with these mutations may be classified as having TRPS III. Our data indicate that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in the TRPS1 gene.

FISH studies in 45 patients with Rubinstein-Taybi syndrome: deletions associated with polysplenia, hypoplastic left heart and death in infancy.

Rubinstein-Taybi syndrome (RTS) is a dominant Mendelian disorder characterised by mental retardation, a typical facies, broad thumbs and short stature. Previous reports indicated that 4-25% of RTS patients have a submicroscopic 16p13.3 deletion of the CBP gene. Using FISH and cosmid probes RT100, RT191 and RT203 we studied 45 RTS patients from Germany, the Czech Republic, Austria and Turkey and found four deletions (8.9%, pooled data including other studies: 11%). All deletions were interstitial; three spanned the CBP gene (RT100-RT203) and one was smaller (RT100 only). Previous studies reported no phenotype-genotype correlation between RTS patients with or without a deletion. Our findings suggest a more severe phenotype. The mean age at presentation was 0.96 years in patients with a deletion as against 11.12 years in those without. Patients A and B with a deletion died in infancy which is rare in RTS and was not observed among the other patients. Patients A and D had accessory spleens, Patient A with hypoplastic left heart, abnormal pulmonary lobulation and renal agenesis. This is the second report of hypoplastic left heart and the first report of polysplenia with RTS. The signs suggest a developmental field defect (disturbance of laterality) either as a newly recognised pattern of RTS, or alternatively a novel contiguous gene syndrome.

Calcium metabolism and growth during early treatment of children with X-linked hypophosphataemic rickets.

UNLABELLED: To evaluate the effect of early treatment on calcium metabolism and growth of infants with X-linked hypophosphataemic rickets (XLH), we enrolled eight infants (one boy) with XLH in a prospective study before and during combined treatment with 40 60 mg/kg per day phosphate and 20-40 ng/kg per day 1,25(OH)2D3 (calcitriol). The duration of treatment ranged from 12 to 68 months (median 27 months). We measured the height and several indices of calcium and bone metabolism before and at intervals of 6 weeks to 3 months thereafter during treatment. The diagnosis XLH was established between the age of 3 to 12 weeks by the detection of elevated alkaline phosphatase activities (n = 8) and urinary hydroxyproline (n = 7), whereas only five patients had also hypophosphataemia. Six of seven untreated patients had decreased 1,25(OH)2 vitamin D levels in serum. During treatment alkaline phosphatase and hydroxyproline decreased to normal or slightly elevated levels, whereas serum phosphate remained below the normal range. Several patients treated with more than 40-50 mg/kg per day phosphate developed secondary hyperparathyroidism. One patient receiving a low dose of 20 ng/kg per day calcitriol had prolonged radiological and biochemical signs of rickets and growth delay. The other patients presented with no or only slightly transient signs of rickets. Three patients developed moderate nephrocalcinosis. The statural growth rate decreased slightly below 2 SDs without a further decrease in two patients and remained within the normal range in the other patients. Only four patients developed moderate leg deformities. CONCLUSIONS: Early treatment with calcitriol at a daily dose of at least 30-40 ng/kg and phosphate at a daily dose of maximal 40-50 mg/kg improves mineral metabolism and seems to obviate severe growth delay and leg deformities.

Deletion mapping by FISH with BACs in patients with partial monosomy 22q13.

Patients with deletions in 22q13 are known to have phenotypic features that include normal or accelerated growth, large hands and feet, hypotonia, delayed psychomotor development and mild facial dysmorphism. To date, very few cases have been investigated by detailed molecular genetic analysis. We have analyzed three new patients with terminal deletions in 22q. We compared the cytogenetic observations with molecular data assessed by fluorescence in situ hybridization and an array of characterized bacterial artificial chromosome recombinants. The shortest region of deletion overlap is localized in 22q13.2-qter distal to the marker D22S94, but the telomeric repeat in the deleted chromosome appears to remain intact. When parental alleles were investigated in two of the three patients, the aberrant homolog was found to be of paternal origin in both cases. Although the deleted region still spans >20 cM, molecular analysis of additional patients and screening for new genes might help in elucidating candidate genes connected with the dysmorphisms defined by deletions of 22q13.

A large family with subtelomeric translocation t(18;21)(q23;q22.1) and molecular breakpoint in the Down syndrome critical region.

We describe a 17-month-old infant with clinical features of Down syndrome and a normal karyotype by standard chromosomal analysis, her two uncles aged 28 and 30 years, respectively, with reduced intelligence and unusual appearance but not apparent Down syndrome, and a severely retarded 6-year-old girl with dysmorphy and epilepsy from the same family. Cytogenetic studies of patients and normal intervening relatives had been carried out at different institutions with normal results. Fluorescence in situ hybridization using whole chromosome painting and unique-copy probes (cosmids) and high-resolution banding revealed a familial subtelomeric translocation of chromosomes 18 and 21, resulting in partial trisomy 21 in the infant and her two uncles, and partial monosomy 21 in the 6-year-old girl. Cytogenetic breakpoints were located in bands 18q23 and 21q22.1, respectively. The molecular breakpoint on chromosome 21 was located between D21S211 (proximal) and D21S1283 (distal) and thus maps within the Down syndrome critical region.

A small deletion of 16q23.1-->16q24.2 [del(16)(q23.1q24.2).ish del(16)(q23.1q24.2)(D16S395+, D16S348-, P5432+)] in a boy with iris coloboma and minor anomalies.

We report on a 5-year-old boy with bilateral coloboma of iris, short stature, moderate developmental delay, and a few minor craniofacial anomalies. High-resolution GTG banding showed a small distal deletion of one chromosome 16 [del(16)(q23.1q24.2)]. Molecular refinement of the deletion breakpoints yielded that the proximal breakpoint at 16q23.1 is located between loci D16S395 (present) and D16S348 (absent). Comparison with previously published cases of deletion 16q demonstrated that the clinical phenotype is not a recognizable 16q- syndrome and different from the two cases of deletions of 16(q22.1 to q24.1) described by Callen et al. [1993]. Evidently, deletion 16(q23.1q24.2) has a milder phenotypic effect than other interstitial and distal 16q deletions.

Evidence for a critical region for penoscrotal inversion, hypospadias, and imperforate anus within chromosomal region 13q32.2q34.

Two unrelated patients with small distal deletions of the long arm of chromosome 13 are described, with shawl scrotum and penoscrotal transposition, penoscrotal hypospadias, a reduced perineum, and anal atresia. The patients have small deletions of 13(q32.2qter) and 13(q32q34), respectively. This report and the literature present evidence for one or possibly more gene(s) within region 13q32.2q34 which regulate the development of the ano-genital structures. The clinical spectrum includes bifid or shawl scrotum, hypospadias, biseptate uterus, malplaced and imperforate anus, and common cloaca.

Delineation of a contiguous gene syndrome with multiple exostoses, enlarged parietal foramina, craniofacial dysostosis, and mental retardation, caused by deletions in the short arm of chromosome 11.

A contiguous gene syndrome due to deletions of the proximal short arm of chromosome 11 is described in eight patients belonging to four families. The main clinical features are multiple exostoses, enlarged parietal foramina, craniofacial dysostosis, and mental retardation. The patients have cytogenetic and/or molecular deletions of chromosome 11p11-p13. These deletions are located between the centromere and D11S914 in a region of approximately 20cM. The present study confirms the presence of a multiple exostoses gene on chromosome 11p. Furthermore, it suggests that the gene for isolated foramina parietalie permagna and genes associated with craniofacial dysostosis and mental retardation reside in the same chromosomal region.

Pseudohypoaldosteronism: family studies to identify asymptomatic carriers by stimulation of the renin-aldosterone system.

Defective aldosterone receptor binding is present in pseudohypoaldosteronism, and sporadic as well as familial cases have been reported. In familial pseudohypoaldosteronism, autosomal dominant as well as autosomal recessive inheritance has been described. The autosomal dominant form is characterized by a relative mild course of the disease and asymptomatic carriers of the defect in these families, whereas the autosomal recessive form is characterized by severe salt-losing symptoms; not uncommonly these families are consanguineous. To date no genetic mutation has been identified in the aldosterone receptor gene of affected patients. Studies to evaluate the biochemical defect and to characterize the inheritance pattern are of major interest for clinical as well as research purposes. Thus we studied the response of the renin-angiotensin-aldosterone system to sodium depletion using a single dose of furosemide. In 5 patients from five nonconsanguineous families and in all available family members the renin and aldosterone levels as well as serum sodium was measured before and after an oral dose of furosemide. The aldosterone receptor binding of peripheral mononuclear leukocytes was determined at the beginning of the study. In three families asymptomatic carriers of the defect could be identified in the baseline state by elevated levels of basal aldosterone and high renin concentration. The levels of renin and aldosterone did not differ between the symptomatic and asymptomatic individuals in these families. Interestingly the aldosterone receptor binding in the asymptomatic carriers of these families was normal. In the other two families, however, the basal hormonal data were normal in all relatives suggesting at first sporadic cases. During sodium depletion with furosemide, renin as well as aldosterone levels rose significantly in 1 parent and a sibling, respectively. In contrast to the first three families the aldosterone receptor binding in these family members was low. We propose to reclassify these family members as asymptomatic carriers and the patients as familial cases. Whether these cases are genetically identical to the 'classical autosomal dominant cases' remains to be seen. It seems that the pathogenesis of pseudohypoaldosteronism is even more heterogeneous than previously thought and factors other than aldosterone receptor binding are crucial and need further identification.

[Contribution of the ophthalmologist to presymptomatic diagnosis of familial adenomatous polyposis (FAP)]. / Beitrag des Ophthalmologen zur präsymptomatischen Diagnostik der familiären adenomatösen Polyposis (FAP).

Familial adenomatous polyposis (FAP) represents a hereditary precancerous condition. Symptoms often appear malignant transformation only. For persons at risk early recognition of gene carriers is essential. Approximately 80% of the patients show congenital hypertrophy of the retinal pigment epithelium (CHRPE) that can be recognized before clinical manifestation of FAP. In order to predict FAP 9 patients and 10 persons at risk from 6 FAP families were examined by endoscopy, molecular genetical and ophthalmological methods. Four patients from two families each had bilaterally 4 CHRPE; four persons at risk did not have CHRPE. This is in accordance with endoscopic and molecular genetic results. The five patients and six persons at risk from the other four families did not have CHRPE, i.e., the percentage of CHRPE in the FAP patients examined was only 45%. Funduscopy permits early identification of gene carriers in families where the FAP patients have CHRPE. CHRPE is not present in persons at risk in these families, it is not necessary to conduct invasive diagnostic measures. Funduscopy should always be done in FAP patients and in persons at risk from CHRPE-positive families. An endoscopic examination should be recommended when CHRPE is observed incidentally in a person with a negative family history for FAP.

DNA, FISH and complementation studies in ICF syndrome: DNA hypomethylation of repetitive and single copy loci and evidence for a trans acting factor.

ICF syndrome (ICFS) is a rare immunodeficiency disorder characterized by instability of the pericentromeric heterochromatin predominantly of chromosomes 1 and 16. DNA methylation studies in two unrelated ICFS patients provide further evidence for a marked hypomethylation of satellite 2 DNA. The ICFS-specific disturbances of chromatin structure take place within the satellite 2 DNA regions, as demonstrated by fluorescence in situ hybridization analysis. Moreover, methylation studies of genomic imprinted loci D15S63, D15S9, and H19 have revealed hypomethylation to different degrees in both patients; this provides evidence for hypomethylation at autosomal single copy loci in ICFS. Cell fusion experiments have revealed a distinct reduction of chromosomal abnormalities in ICFS cells after fusion with normal cells, suggesting that the abnormalities are caused by the loss of function of an as yet unknown trans acting factor. Although it is now clear that wide-spread DNA hypomethylation is a characteristic feature of ICFS, neither the cause and mechanism of hypomethylation nor their relationship to the clinical symptoms is known. We speculate that a phenotypic effect might result from tissue-dependent abnormal gene expression and/or from a possible structural disturbance of DNA domains, which, with respect to the immunodeficiency, partially prevents the normal somatic recombinations in immunologically active cells.

Familial pseudohypoaldosteronism: a review on the heterogeneity of the syndrome.

Pseudohypoaldosteronism is thought to be a rare salt-losing disorder, caused by resistance to the action of aldosterone. Defective aldosterone receptor binding is present in familial as well as sporadic cases and it has been suggested that the pathogenesis is due to a defect in the aldosterone receptor system. To date, however, molecular genetic analysis has been unable to identify a mutation in the aldosterone receptor gene itself. We have reviewed the findings in patients with pseudohypoaldosteronism, for clues which might enable us to identify the underlying pathogenesis. Although aldosterone receptor binding is regularly decreased or absent in monocytes of patients with pseudohypoaldosteronism, in some patients receptor protein can be detected with a fluorescence-labeled antibody. Receptor protein was detected in patients from familial autosomal dominant families and in sporadic cases, but was undetectable in two patients with the familial recessive form. To further elucidate the pattern of inheritance we studied the response of the renin-angiotensin-aldosterone system to the stimulation by sodium depletion in the familial autosomal dominant form and in two families with sporadic cases. In both "sporadic" families investigated, one parent and one sibling had an exaggerated response of renin and aldosterone to sodium depletion indicating a defect of sodium conservation apparent only during stress, leading to reclassification as familial cases. No additional family member in the "classical" autosomal dominant families responded abnormally to sodium depletion. These findings indicate that pseudohypoaldosteronism is unusually heterogeneous in its clinical, biochemical, and genetic presentations and findings and suggest that its pathogenesis is heterogeneous as well.

Six cases of 7p deletion: clinical, cytogenetic, and molecular studies.

To date, 32 cases of partial 7p monosomy have been described, 14 of which have been associated with craniosynostosis (CRS). There is considerable variation in the size and location of the deleted segment. However, CRS appears to be consistently associated with either a deletion or partial deletion 7p21-->7p22 or more rarely a deletion of 7p13-->7p14. Analysis of a panel of six 7p deletion cases (three with CRS) was undertaken using informative DNA probes, in order to characterize and define the extent of the deletions at the molecular level. There were five de novo deletions and one resulting from the unbalanced product of a paternal balanced insertion. The putative proximal CRS locus at 7p13-->7p14 does not appear to be allelic with Greig cephalopolysyndactyly syndrome. Three probe positions have been refined: pJ5.11 (D7S10) previously mapped to 7p14-->pter does not appear to map proximal to p15; TM102L (D7S135) does not map distal to p22; CRI-P137 (D7S65) maps distal to 7p13.

Transient pseudohypoaldosteronism in obstructive renal disease with transient reduction of lymphocytic aldosterone receptors. Results in two affected infants.

We report two patients with transient pseudohypoaldosteronism due to obstructive renal disease. Both patients presented with a salt-losing episode simulating adrenal insufficiency. In one patient, transient reduction of aldosterone receptors could be documented, while in the second patient the clinical and biochemical parameters were consistent with transient pseudohypoaldosteronism. Aldosterone receptors were normal in both patients when studied after the surgical correction of the obstruction.

Colloid cyst of the third ventricle with XYY-syndrome.

Case presentation of an intra-uterine diagnosed third ventricle colloid cyst in a male with XYY-Syndrom. The inner cellular cover of cyst was composed by flat or cuboidal to columnar epithelium, which beared cilia in some areas. Other cells of the inner cover showed protrusions of cytoplasm, which extended into the cyst cavity. The cyst wall showed loosely arranged fibrous connective tissue, some Plasmocytes, and a few cells with granulated plasma. The histogenesis of this cyst was suggested immunohistologically from primitive neuroepithelial structures. According to sonographic findings an intra-uterine diagnosed intracerebral cyst should be a cause to search other malformations.

[Contribution to hypochondrogenesis]. / Beitrag zur Hypochondrogenese.

Hypochondrogenesis is one of non-viable skeleton dysplasiae which recently has been delimited as an entity of its own and with its classification between spondylo-epiphysary dysplasia and achondrogenesis. An accurate differential diagnosis requires specialised histo-pathological investigations of the patient's cartilage tissue. Five new observations compared to a classical case of dysplasia spondylo-epiphysaria congenita are added to the references made in literature.

Stimulation of nitrogen and whole-body protein metabolism in growth hormone-deficient children by recombinant human growth hormone: relationship to growth.

The effect of a mammalian-cell-derived recombinant human growth hormone (rhGH) on nitrogen and whole-body protein metabolism was assessed in 12 children with complete growth hormone (GH) deficiency. All the patients received single oral doses of 15N-glycine (95 atom % 15N), 20 mg/kg body weight, prior to and following 7 days of treatment with rhGH, 1.7 IU/m2 body surface area (BSA) per day, administered subcutaneously. Prior to rhGH, mean urinary 15N-nitrogen excretion was 42.8 +/- 8% of the administered dose, which fell significantly to 22.8 +/- 7% during rhGH administration (p < 0.0001). Stimulation of protein metabolism by rhGH resulted in a protein net gain rate of 1.1 +/- 0.4 g/kg/day, which was significantly higher than the 0.6 +/- 0.5 g/kg/day rate seen prior to rhGH (p < 0.001). In patients subsequently placed on daily subcutaneous injections of rhGH 1.7 IU/m2 BSA, mean height velocity standard deviation score (HV SDS) for chronological age significantly increased from -3.8 +/- 2.6 to +8.5 +/- 3.1 and +3.3 +/- 2.2, during the 1st and 2nd years of treatment, respectively. However, there was no correlation between the long-term response to rhGH treatment and the short-term changes in nitrogen or protein metabolism in GH-deficient children.