Spondylocostal/spondylothoracic dysostosis: the clinical basis for prognosticating and genetic counseling.

Short trunk dwarfism involving skeletal anomalies of vertebrae and ribs have been reported under various names. Both dominant and recessive and severe and mild conditions are found. We report on a patient without a severe handicap by age 3 years despite severe involvement of the thorax at birth, suggesting that a more complete classification of such anomalies is needed for counseling. We have used an objective method to classify 39 informative patients from the literature, 35 said to have a recessive disease and four a dominant one. Two patients with the costovertebral segmentation defect with mesomelia (COVESDEM) syndrome were added for comparison with our patient. The results of cluster analysis show that there are three phenotypic groups of patients. Cluster 1 contains 19 patients with a severe form of spondylothoracic dysplasia; cluster 2 includes patients with a mild autosomal recessive and a dominant type; cluster 3 groups the two sibs with the COVESDEM syndrome and our patient. One must be cautious in advising families of the prognosis for a child with severe structural chest deformity since it may not be severe from a functional point of view. More data are needed for complete discrimination between the mild autosomal recessive and dominant forms.

The hand profile on de Lange syndrome: diagnostic criteria.

The hand pattern profiles of 18 previously published and 10 new cases of de Lange syndrome were compared to those of cases referred as suspects, but judged clinically and by numerical taxonomic methods not to have de Lange syndrome (non-de Lange). Based on a Poznanski metacarpophalangeal profile of the 2 groups of patients, a simple scoring system using 11 measurements was devised using the 16 most marked differences within and between metacarpals and phalanges. Of the metacarpals, the first is shorter than the second, third, fourth, or fifth; and the second and fifth are shorter than the third or fourth. Of the middle phalanges, the third and fourth are shorter than the respective metacarpal and than the second and fifth middle phalanx. Of the distal phalanges, the fifth is shorter than the second. The mean Z score for these 11 measurements is further below normal in the de Lange group than in the non-de Lange group. All 11 non-de Lange patients had a score less than 17, and all 28 de Lange patients had a score of 18 or more.

Diagnosis of chromosome 3 duplication q23----qter, deletion p25----pter in a patient with the C (trigonocephaly) syndrome.

The cells of a deceased patient previously reported to have the C (trigonocephaly) syndrome were reinvestigated because his phenotype resembled that of a patient with a duplication-deficiency of chromosome 3. This diagnosis was confirmed using fibroblasts grown from frozen cells, and his mother was shown to carry an inversion of chromosome 3 in her peripheral blood leukocytes. His findings are compared to those of another patient with the C trigonocephaly syndrome with normal chromosomes and to others from the literature. At least one other patient from the literature has a phenotype compatible with "3q duplication syndrome."

Definition and diagnosis of the Brachmann-De Lange syndrome.

We have classified patients referred for suspicion of the Brachmann-De Lange syndrome (BDLS) into two groups using techniques of numerical taxonomy. Patients with the syndrome share an array of abnormal characteristics, and those without it have different abnormal characteristics. A group of 30 characters that best distinguish the two groups of patients was used to construct a diagnostic index. The index score is expected to divide 99% of patients into those with and without the syndrome, leaving 1% in a "zone of doubt." All 46 patients used to construct the index and 16 new patients had scores in either the BDLS or non-BDLS range and none were in the zone of doubt. A previously published index using metacarpal-phalangeal measurements, although less discriminatory, confirmed our findings in 84% of 25 patients tested, the remainder having scores in the zone of doubt for that index.

A taxonomic approach to the del(4p) phenotype.

The findings of 23 patients with the del(4p) phenotype are compared systematically. Three patients with a small deletion evident only on analysis of extended chromosomes have a phenotype comparable to 13 patients with a more extensive chromosomal deletion. Two patients with no detectable deletion also fit into the phenotypic spectrum of patients with del(4p), suggesting the same etiology. Five patients with fewer typical and more atypical findings probably represent a heterogeneous group of other syndromes. Numerical analysis of the phenotype allows one to identify patients who most likely have a deletion requiring a more intensive cytogenetics analysis.

Waardenburg syndrome--penetrance of major signs.

We have estimated that 83% of individuals carrying the gene for Waardenburg syndrome type I show penetrance of the gene as measured by dystopia canthorum. This is lower than previous estimates, which failed to consider the frequency of equivocal dystopia in the general population. The addition of three other major signs (hearing loss, white forelock, and premature graying of the hair or vitiligo) does not substantially increase the discrimination of gene carriers (85% versus 83%). We estimate that about 75% of the first-degree relatives of probands can be assigned as normal or a gene carrier on the basis of the four major signs.

Noonan syndrome: the changing phenotype.

Among the multiple congenital anomalies (MCA) syndromes, the Noonan syndrome (NS) is a cardiofacial syndrome in which affected individuals may be short and mildly mentally retarded. Autosomal dominant inheritance of Noonan syndrome with variable expressivity has been documented in many families. Genetic heterogeneity has been postulated in Noonan syndrome because of the wide phenotypic variability, the relatively high incidence, and the occasional recurrence in sibs with apparently normal parents. Clinical variability is usual in autosomal dominant disorders, and mildly affected individuals may be difficult to recognize as gene carriers. Thus, a family with two or more affected children may simulate autosomal recessive inheritance. We have studied serial and family photographs of NS individuals in order to assess the likelihood of gene carriers' being missed in genetic studies. We have confirmed wide clinical variability within families, and more importantly, we have documented marked change of phenotype with age from the newborn period, infancy, childhood, and adolescence to adulthood. Manifestations in adults may be subtle and some without a known heart defect or other medically significant problems may have been considered normal in the past. Our study, while not ruling out causal heterogeneity, suggests that the change of phenotype with age may have been falsely perceived as clinical heterogeneity. A particular and subtle phenotype must be searched for in parents of affected children.

Synthesis of dehydro-oogoniol, a female-activating hormone of Achlya: the progesterone route.

The structure of dehydro-oogoniol (3 beta,11 alpha,15 beta,29-tetrahydroxystigmasta-5,24(28)(E)-dien-7-one), a female-activating hormone of the water mold Achlya, has been confirmed by synthesis. The starting material was progesterone, which was converted to the 11 alpha, 15 beta-dihydroxy derivative by microbiological hydroxylation with Aspergillus giganteus (ATCC 10059). The side chain was constructed in a stepwise manner by means of Wittig and Horner-Emmons reactions, and the C-7 ketone was then introduced by allylic oxidation. The biological activity of the synthetic compound was the same as that of the natural hormone.

Diagnostic value of serum creatine kinase and lactate dehydrogenase isoenzyme determinations for monitoring early cardiac damage in rats.

Serum activities of creatine kinase (CK, EC 2.7.3.2) and CK isoenzymes, lactate dehydrogenase (LDH, EC 1.1.1.27) and LDH isoenzymes, alpha-hydroxybutyrate dehydrogenase (alpha-HBDH, no EC) and the LDH/alpha-HBDH ratio were studied following a single s.c. application of 5-250 mg isoproterenol/kg body weight (b.w.) in rats. Measurements of the serum enzymes and histological and enzyme-histochemical examinations of hearts were performed 2, 4, 6, 8 and 24 h after treatment. A drastic increase in serum levels of the isoenzymes CK-MB, LDH1, LDH2 and alpha-HBDH and decrease in the ratio LDH/alpha-HBDH were observed from 2 h onwards after isoproterenol application in all dose groups, the maximum effect being after 4-8 h. Focal cellular injury in the myocardium could also be observed from 2 h onwards after isoproterenol application by an enzyme-histochemical method using nitro blue tetrazolium (NBT) whereas the earliest histological alterations using haematoxylin and eosin (HE) stain could be detected 6 h after treatment. A dose-dependent effect as to enzyme values as well as to myocardial necrosis was observed 24 h after isoproterenol application. No kidney damage could be detected on the basis of serum urea nitrogen and histological examinations. Thus, measurement of serum activities of CK-MB isoenzyme alone or LDH1-2 isoenzymes in combination with other tests to exclude kidney damage are valuable indicators of cardiac lesions in rats.

Increased morphological variants in children with learning disabilities.

Previous studies have shown that children with learning disabilities have more morphological variants or anomalies than normal children, suggesting that the morphological and central nervous system effects may be the result of the same prenatal factors. The morphological variants were assumed to have arisen in the first 3 months of prenatal development, which may not be so. We have partitioned variants into those that probably arise early in fetal development ("early" variants) and those that could arise later and could be due to altered growth ("late" variants). There was an increase in both "early" and "late" variants but only that the "late" variants was statistically significant. Although the method of measuring one "early" variant (dermal patterns) was sensitive enough to detect mild disturbances in children with isolated congenital heart disease, such a disturbance was not found in our group of learning-disabled patients. Our findings suggest that the developmental disturbances resulting in morphological variants may act later in prenatal development than was previously believed. This information may be helpful in searching for clues to the etiology of this heterogeneous group of disabilities.

A screening test for patients suspected of having Turner syndrome.

An index has been devised using dermatoglyphics and selected physical traits to screen for patients suspected of having Turner syndrome. About 60% of females with and without Turner syndrome can be diagnosed as having or not having the syndrome with a 98% or greater probability. The patient's score on the index, expressed in probability, can be used to decide whether chromosome studies should be done. Using the approach demonstrated in this pilot study, the discriminative power can be increased by adding more features and by enlarging the sample to permit division of features into more discriminating classes.

The Williams syndrome: objective definition and diagnosis.

Fifty-two patients referred for suspicion of the Williams syndrome have been evaluated and divided into those with and without the syndrome by numerical analysis. A diagnostic index using 50 characters separates patients into two groups with an expected accuracy of 99%. An index using 40 of the characteristics is expected to be applicable to young infants without a substantial decrease in accuracy.

Differential diagnosis of the Williams and the Noonan syndromes.

A diagnostic index has been devised to distinguish between the Noonan and the Williams syndromes. Twins from the literature reported as having the Williams syndrome more likely represent the Noonan syndrome.

Clinical confusion of the Noonan syndrome with the Börjeson-Forssman-Lehmann syndrome.

The diagnosis of Börjeson-Forssman-Lehmann syndrome in a patient reported by Veall et al. (1979) is challenged. The clinical findings were compared with those in 32 patients with the Noonan syndrome using the extensive description, dermatoglyphics, photographs and anthropometric measurements provided in the paper. The patient's findings are compatible with the Noonan syndrome based on his overall phenotypic similarity to the 32 patients, even though the severity of his mental retardation is atypical.

A diagnostic index for Down syndrome.

A simple and effective index for the diagnosis of Down syndrome is presented. It makes use of 12 characters with from two to nine states. The simple format allows persons with limited knowledge of the characters to use it. Simplicity was attained by combining character states when this did not result in a loss of discrimination and by avoiding characters that were redundant, subject or difficult to evaluate. A combination of characters that occur frequently in Down syndrome (wide applicability and characters that have a high relative frequency (high probability) was used. Additional data from comparable samples were used to calculate more representative scores for some characters. Over 82% of suspected cases may be diagnosed as having or not having Down syndrome with 99.9% confidence. Conditional probabilities for the various scores are provided. Individuals whose scores are in the Down or non-Down zones have a 98.7% probability or greater of having or not having the syndrome, respectively. The index is more effective than others as measured both by the percentage of individuals with and without Down syndrome whose scores fall into distinct zones (overlap method) and by the percentage with Down syndrome who have positive scores and controls who have negative scores (single point classification).

Formal analysis of dysmorphism: objective methods of syndrome definition.

A set of descriptors was developed and used to code patients with 4p or 9p monosomy or trisomy, "blind" as to their karyotype. Techniques of numerical taxonomy were used to classify the patients on the basis of their phenotypic resemblance. As expected, the results confirm strong phenotype-karyotype correlations. When cytogenetic interpretations are uncertain, the phenotypic findings may confirm or refute the interpretations. The approach has practical implications, providing further knowledge of phenotypic effects of specific chromosomal segments, which will aid cytogeneticists in their search for karyotypic defects. More important, the results also serve as an excellent model for developing strategies for the classification of syndromes of unknown etiology.

The Marshall and Stickler syndromes: objective rejection of lumping.

To answer the question of whether nosological splitting of the Marshall and Stickler syndromes is justified at the phenotypic level, we surveyed published reports on the two syndromes and applied an objective method to determine this. A set of 18 patients with clinical description, photographs, and radiographs was used to tabulate a list of 53 signs. Cluster analysis using these signs showed that there are two groups of patients with different phenotypes. An index score based on the 20 most discriminating signs was applied to other reported patients and the authors' diagnosis confirmed. There is therefore no objective reason to consider that these two syndromes are not separate dominant disorders with variable expressivity.

The distorted shell method for clustering for syndrome classification.

Syndrome classification may be described as the arrangement of individuals into groups on the basis of their phenotypic resemblance. This paper describes how phenotypic resemblance may be quantified and demonstrates a numerical method called distorted shell clustering, which isolates groups of phenotypically similar individuals representing syndromes. This new method takes into consideration apparent biological properties of syndromes. It allows for overlapping phenotypes between syndromes, and differing character association and variability within syndromes. This method is compared to four other clustering methods by using suspects for a syndrome of known etiology (Down syndrome). The numerical results based on the phenotype then can be compared with the actual diagnosis. Only the distorted shell method classifies patients, without error, into two major clusters: the Down and the non-Down, while maintaining a high level of efficiency.

A diagnostic index for Down syndrome.

We have made use of eight phenotypic findings of Down syndrome to develop an effective diagnostic index. We estimate that about 95% of patients who are suspected of having the syndrome can be categorized as having or not having it with 99.9% confidence. One can thereby make a fast clinical diagnosis on the majority of suspects before karyotyping is complete, allowing one to inform parents soon after birth and, in some instances, to make medical decisions about life-threatening defects. Furthermore, one can avoid the expense of chromosome studies on most patients who do not have the syndrome, unless there are other indications for chromosome studies. The eight features used in the index include three dermatoglyphic traits (hallucal and forefinger pattern, and palmar triradius), two measurements of physical traits (ear length and internipple distance), and three other clinical findings (Brushfield spots, wide-spaced first toe, and excess back neck skin).

A methodology for establishing a diagnostic index for syndromes of unknown etiology.

A method has been developed to test for heterogeneity in syndromes of unknown etiology and to distinguish between patients with and without the syndrome. The validity of the method was tested on a group of patients suspected of having a syndrome that can be diagnosed by other means (Down syndrome), and was found to be effective. The method was then applied to a group of patients suspected of having a syndrome of unknown etiology (de Lange). It was shown that the group appears to be heterogeneous. A preliminary diagnosis of having or not having the syndrome was made in about 80% of the patients.