Further Evidence of Contrasting Phenotypes Caused by Reciprocal Deletions and Duplications: Duplication of NSD1 Causes Growth Retardation and Microcephaly.

Microduplications of the Sotos syndrome region containing NSD1 on 5q35 have recently been proposed to cause a syndrome of microcephaly, short stature and developmental delay. To further characterize this emerging syndrome, we report the clinical details of 12 individuals from 8 families found to have interstitial duplications involving NSD1, ranging in size from 370 kb to 3.7 Mb. All individuals are microcephalic, and height and childhood weight range from below average to severely restricted. Mild-to-moderate learning disabilities and/or developmental delay are present in all individuals, including carrier family members of probands; dysmorphic features and digital anomalies are present in a majority. Craniosynostosis is present in the individual with the largest duplication, though the duplication does not include MSX2, mutations of which can cause craniosynostosis, on 5q35.2. A comparison of the smallest duplication in our cohort that includes the entire NSD1 gene to the individual with the largest duplication that only partially overlaps NSD1 suggests that whole-gene duplication of NSD1 in and of itself may be sufficient to cause the abnormal growth parameters seen in these patients. NSD1 duplications may therefore be added to a growing list of copy number variations for which deletion and duplication of specific genes have contrasting effects on body development.

Case of partial duplication 2q3 with characteristic phenotype: rare occurrence of an unbalanced offspring resulting from a parental pericentric inversion.

We report on a male infant with partial trisomy 2q (q34-->qter) resulting from a maternal pericentric inversion of chromosome 2 (p25. 2q34). The infant had clinical findings similar to the characteristic phenotype associated with a partial duplication of chromosome 2q3. Carriers of pericentric inversions of chromosome 2 have an increased risk of pregnancy loss but have only rarely been reported to have a liveborn offspring with an unbalanced chromosome constitution. This case further confirms the risks associated with a pericentric inversion of chromosome 2 and is the second report with manifestations of the trisomy 2q3 phenotype.

Neonatal progeroid (Wiedemann-Rautenstrauch) syndrome: report of five new cases and review.

The neonatal progeroid syndrome (NPS), or Wiedemann-Rautenstrauch, is a rare autosomal recessive disorder comprised of generalized lipoatrophy except for fat pads in the suprabuttock areas, hypotrichosis of the scalp hair, eyebrows, and eyelashes, relative macrocephaly, triangular face, natal teeth, and micrognathia. We report on 5 new patients who demonstrate phenotypic variability and who represent the single largest series of NPS reported to date. Two of the patients are from an African-American kindred, an ethnic occurrence not reported previously. The fact that there are 2 pairs of sibs among the 5 patients further supports that NPS is an autosomal recessive condition. This report also includes a review of the previously reported 16 patients and compares them with the 5 new patients. Abnormalities in endocrine and lipid metabolism were found in 3 of 5 patients. Skeletal findings in 2 of our patients demonstrated some new findings as well as the typical radiological abnormalities previously noted in NPS. It is apparent, based on the 21 cases, that mild to moderate mental retardation is common in NPS. Long term follow-up of patients with NPS should provide more information relative to their ultimate psychomotor development. NPS is usually lethal by 7 months; however, on rare occasions, patients have survived into the teens. Our 3 surviving patients range in age from 16-23 months. Variability in the phenotype of NPS is clear; however, the phenotype remains distinct enough to allow a secure diagnosis.

Case of partial trisomy 9p and partial trisomy 14q resulting from a maternal translocation: overlapping manifestations of characteristic phenotypes.

We report on a female infant with partial trisomy 9p (pter-->p13) and partial trisomy 14q (pter-->q22) resulting from a 3:1 segregation of a maternal reciprocal translocation (9;14)(p13;q22). Both trisomy 9p and partial trisomy 14q have been described as recognized phenotypes with characteristic patterns of anomalies. This patient appears to be the first reported with a partial duplication of both 9p and 14q resulting in an overlapping phenotype including minor facial anomalies, cleft palate, and hand-foot anomalies. However, the facial findings were more pronounced than commonly observed in cases with only one or the other duplicated chromosome regions, resulting in a distinctive appearance.

Color vision deficits and laser eyewear protection for soft tissue laser applications.

PURPOSE: Laser safety considerations require urologists to wear laser eye protection. Laser eye protection devices block transmittance of specific light wavelengths and may distort color perception. We tested whether urologists risk color confusion when wearing laser eye protection devices for laser soft tissue applications. MATERIALS AND METHODS: Subjects were tested with the Farnsworth-Munsell 100-Hue Test without (controls) and with laser eye protection devices for carbon dioxide, potassium titanyl phosphate (KTP), neodymium (Nd):YAG and holmium:YAG lasers. Color deficits were characterized by error scores, polar graphs, confusion angles, confusion index, scatter index and color axes. Laser eye protection device spectral transmittance was tested with spectrophotometry. RESULTS: Mean total error scores plus or minus standard deviation were 13+/-5 for controls, and 44+/-31 for carbon dioxide, 273+/-26 for KTP, 22+/-6 for Nd:YAG and 14+/-8 for holmium:YAG devices (p <0.001). The KTP laser eye protection polar graphs, and confusion and scatter indexes revealed moderate blue-yellow and red-green color confusion. Color axes indicated no significant deficits for controls, or carbon dioxide, Nd:YAG or holmium:YAG laser eye protection in any subject compared to blue-yellow color vision deficits in 8 of 8 tested with KTP laser eye protection (p <0.001). Spectrophotometry demonstrated that light was blocked with laser eye protection devices for carbon dioxide less than 380, holmium:YAG greater than 850, Nd:YAG less than 350 and greater than 950, and KTP less than 550 and greater than 750 nm. CONCLUSIONS: The laser eye protection device for KTP causes significant blue-yellow and red-green color confusion. Laser eye protection devices for carbon dioxide, holmium:YAG and Nd:YAG cause no significant color confusion compared to controls. The differences are explained by laser eye protection spectrophotometry characteristics and visual physiology.

Predictive value of fetal ultrasonography in the diagnosis of a lethal skeletal dysplasia.

BACKGROUND: Certain ultrasonographic findings identified in a fetus suspected of having a skeletal dysplasia may be predictive of a lethal outcome. METHODS: We evaluated 27 fetuses suspected of having a skeletal dysplasia using targeted ultrasonography between 16 and 31 weeks' gestation. Clinical examination and skeletal radiography were done after delivery. RESULTS: A skeletal dysplasia was confirmed and a diagnosis established in all but one case. The skeletal dysplasia was lethal in 23 cases and, in each case, the outcome was accurately predicted prenatally; however, three of the infants survived several months. In 11 of the 23 cases (48%), the specific diagnosis was correctly determined before birth. Ultrasonographic findings not considered to reflect a lethal outcome, were accurately predicted in two other cases. In an additional two, sonographic examination suggested a lethal osteochondrodysplasia, though both survived. Findings consistent with a lethal skeletal dysplasia included a femur length < 1st centile, combined with either a bell-shaped thorax, decreased bone echogenicity, or both. Using these criteria provided a positive-predictive value for neonatal deaths of 80% (20/25), and 92% (23/25) if the three that died in infancy were included. CONCLUSIONS: In the fetus suspected of having a skeletal dysplasia, certain findings on targeted ultrasonography frequently are predictive of a lethal outcome; the ability to predict this appears greatest when more than one of these abnormalities is present.

Atypical case of Smith-Lemli-Opitz syndrome: implications for diagnosis.

Smith-Lemli-Opitz (SLO) syndrome is an autosomal recessive disorder comprised of recognizable facial abnormalities, growth retardation, and multiple congenital anomalies, commonly involving genitalia, second and third toe syndactyly, and cleft palate. The condition is associated with hypocholesterolemia and elevated levels of 7-dehydrocholesterol (7DHC) resulting from deficient activity of the enzyme 7-dehydrocholesterol reductase. The clinical spectrum of SLO ranges from individuals with mental retardation and minor anomalies to those with major structural defects and early or even prenatal lethality. Low maternal serum unconjugated estriol (uE3) levels and a variety of fetal ultrasound anomalies have been identified in affected pregnancies, and prenatal diagnosis is possible by measurement of amniotic fluid 7DHC levels in pregnancies known to be at risk because of a previously affected child. We report on a pregnancy with low maternal uE3 level, abnormal antenatal ultrasound findings including limb deformities, ventriculomegaly, and hydrops fetalis, and a normal 46,XY karyotype. The infant died at birth. At autopsy the infant had hydrops, unusual face, cleft palate, genital abnormalities, Dandy-Walker malformation, and absence of toe syndactyly. Tests performed on cultured skin fibroblasts showed elevated levels of 7DHC and abnormalities of cholesterol biosynthesis characteristic of the metabolic defect that causes SLO. The atypical findings of hydrops, uncharacteristic facial appearance, and absence of toe syndactyly in this case additionally illustrates the wide phenotypic spectrum of SLO and the need for a high index of suspicion for a disorder with great clinical variability. Identification of another affected pregnancy with a low maternal uE3 level and abnormal fetal ultrasound findings in the presence of a normal karyotype lends additional support for consideration of prenatal biochemical testing for SLO in pregnancies with these findings, including pregnancies not previously known to be at risk.

Molecularly proven hypochondroplasia with cloverleaf skull deformity: a novel association.

We report on a case of cloverleaf skull deformity in a patient with hypochondroplasia, a disorder which has not been previously associated with this anomaly. Hypochondroplasia is a bone dysplasia caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Cloverleaf skull is a trilobar skull deformity which is etiologically and genetically heterogeneous and occurs in association with a number of disorders which result from mutations in the fibroblast growth factor receptor genes. Our patient demonstrated one of the common FGFR3 mutations identified in hypochondroplasia, a C-to-A change at nucleotide 1620 (C1620A) in the tyrosine kinase domain. The occurrence of a cloverleaf skull deformity appears to represent an example of variable expressivity in hypochondroplasia and suggests that additional factors other than a specific mutation can modify the phenotype in this disorder. In addition, identification of another FGFR mutation associated with cloverleaf skull further illustrates the genetic heterogeneity of this anomaly.

Color vision deficits during laser lithotripsy using safety goggles for coumarin green or alexandrite but not with holmium:YAG laser safety goggles.

PURPOSE: Laser lithotripsy requires urologists to wear laser eye protection. Laser eye protection devices screen out specific light wavelengths and may distort color perception. This study tests whether urologists risk color confusion when wearing laser eye protection devices for laser lithotripsy. MATERIALS AND METHODS: Urologists were tested with the Farnsworth Dichotomous Test for Color Blindness (D-15) and the Farnsworth-Munsell 100-Hue Test (FM-100) without (control) and with laser eye protection devices for coumarin green, alexandrite and holmium:YAG lasers. Error scores were tabulated. The pattern of color deficits was characterized with confusion angles, confusion index (C-index), scatter index (S-index) and color axes. Laser eye protection devices were tested with spectrophotometry for spectral transmittance and optical density. RESULTS: The D-15 transposition errors (mean plus or minus standard deviation) for control, holmium:YAG, alexandrite and coumarin green laser eye protection were 0 +/- 0, 0 +/- 0, 0.3 +/- 0.5 and 6.4 +/- 1.6, respectively (p = 0.0000001). The FM-100 error scores (mean plus or minus standard deviation) were 20 +/- 15, 20 +/- 14, 91 +/- 32 and 319 +/- 69, respectively (p = 0.0001). The confusion index scores indicated a mild color confusion for the alexandrite and pronounced color confusion for the coumarin green laser eye protection. The confusion angles and scatter indexes mimicked a congenital blue-yellow deficit for coumarin green laser eye protection. Color axes showed no significant deficits for control or holmium:YAG laser eye protection in any subject, red-green axis deficits in 3 of 6 tested with alexandrite and blue-yellow axis deficits in 12 of 12 tested with coumarin green (p < 0.001). Spectrophotometry showed that laser eye protection for coumarin green blocks light less than 550 nm., alexandrite blocks light greater than 650 nm. and holmium:YAG blocks light greater than 825 nm. CONCLUSIONS: Laser eye protection for coumarin green causes pronounced blue-yellow color confusion, whereas alexandrite causes mild red-green color confusion among urologists, holmium:YAG causes no significant color confusion compared to controls. The differences are explained by laser eye protection spectrophotometry characteristics and visual physiology.

Expansion of the phenotype in Hennekam syndrome: a case with new manifestations.

We report on a female with lymphedema, facial anomalies, intestinal lymphangiectasia, and moderate mental retardation consistent with the diagnosis of Hennekam syndrome. In addition, she had a number of other anomalies not previously described in this autosomal recessive disorder, including a congenital heart defect, atretic ear canals, vesicoureteral reflux, and rectal prolapse.

XY gonadal dysgenesis associated with a multiple pterygium syndrome phenotype.

Most phenotypic females with an XY male karyotype do not have significant extragenital anomalies; however, some patients with additional abnormalities have been described. We report on an individual with XY gonadal dysgenesis, mental retardation, microcephaly, growth retardation, and multiple pterygia. Although not previously reported, the possible relationship between these findings is discussed in the context of evident heterogeneity of XY gonadal dysgenesis.

Anophthalmia, intracerebral cysts, and cleft lip/palate: expansion of the phenotype in oculocerebrocutaneous syndrome?

We report on a patient with multiple congenital anomalies including anophthalmia, cleft lip and palate, and central nervous system anomalies similar to the case reported by Leichtman et al. [1994: Am J Med Genet 50:39-41] and to oculocerebrocutaneous (Delleman) syndrome. Although the two cases and those with oculocerebrocutaneous syndrome may represent separate but overlapping entities, our patient and the case described by Leichtman et al. [1994: Am J Med Genet 50:39-41] may represent a more severe form of oculocerebrocutaneous syndrome.

An increased incidence of haemangiomas in infants born following chorionic villus sampling (CVS).

The incidence of haemangiomas was ascertained by questionnaire in infants born to 578 consecutive CVS patients and 445 consecutive mid-trimester amniocentesis patients seen at a single institution between 1 January 1989 and 31 May 1991. The incidence of 7.4 per cent reported in the amniocentesis group was comparable to previous estimates of the incidence of haemangiomas in the general population. In contrast, a 21.1 per cent incidence, three-fold higher than that observed in the amniocentesis group, was observed among CVS-exposed infants (P < 0.001). This increased incidence was largely confined to patients undergoing a transcervical procedure. No correlation was observed between the incidence of haemangiomas and gestational age at sampling, sample size, number of sampling attempts, or a history of bleeding following the procedure.

Microcephaly, lymphedema, and chorioretinal dysplasia: report of two additional cases.

In recent years, several patients with microcephaly, lymphedema and chorioretinal dysplasia have been described. We have studied two additional patients with similar findings. The question of whether microcephaly with lymphedema and microcephaly with chorioretinal dysplasia and lymphedema are distinct entities remains unanswered. Identification of other patients in the future may provide additional information.

Hematological and biochemical changes during a short triathlon competition in novice triathletes.

Short-course 'sprint' triathlons have become popular in recent years, often as a precursor to the longer full-course triathlons. We undertook a study investigating the haematological and biochemical changes that occur in novice triathletes between the start and finish and after each of the three legs of a short sprint triathlon involving swimming, cycling and running. The changes that occurred in the triathlon included a significant (P less than 0.003) decrease in weight from 71.7 kg, SD 7.9 to 70.3 kg, SD 7.6. Throughout the time span of the triathlon, the white blood cell count increased significantly (P less than 0.001), as did the platelet count (P less than 0.005) and plateletcrit (P less than 0.001). There were no significant changes during the period of the race in any of the other haematological variables measured. The biochemical variables measured were glucose, triglycerides, sodium, potassium, calcium, lactate dehydrogenase, creatinine and aspartate aminotransferase. Triglyceride, calcium and potassium values did not change between the pre- and post-race samplings. All other biochemical parameters showed a significant change (P less than 0.05 or better). Changes that occurred in the haematological and biochemical parameters between stages were many and varied. There was also a significant change in plasma volume during the swimming event (P less than 0.001), but this returned to normal during the later stages of the triathlon. In conclusion the changes that occurred during the triathlon were many and were similar to those reported elsewhere in the literature for longer events.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the effect of high and low doses of methadone on treatment outcome.

The results of a 2-year-study of the relationship between methadone dosage and treatment outcome are reported. For discharged patients, higher doses of methadone were significantly related to successful treatment and lower doses to treatment failure. Based on these findings and the review of literature as well as the senior author's clinical experience, a theoretical formulation is offered to provide a rationale for methadone maintenance treatment. The tenability of the formulation is readily testable by clinical research.