Boris G. Kousseff

Uniparental isodisomy of chromosome 14 in two cases: An abnormal child and a normal adult

Uniparental disomy (UPD) of a number of different chromosomes has been found in associated with abnormal phenotypes. A growing body of evidence for an imprinting effect involving chromosome 14 has been accumulating. We report on a case of paternal UPD of chromosome 14 studied in late gestation due to polyhydramnios and a ventral wall hernia. A prenatal karyotype documented a balanced Robertsonian 14:14 translocation. The baby was born prematurely with hairy forehead, retrognathia, mild puckering of the lips and finger contractures. Hypotonia has persisted since birth and at age one year, a tracheostomy for laryngomalacia and gastrostomy for feeding remain necessary. Absence of maternal VNTR polymorphisms and homozygosity of paternal polymorphisms using chromosome 14 specific probes at D14S22 and D14S13 loci indicated paternal uniparental isodisomy (pUPID). Parental chromosomes were normal. We also report on a case of maternal UPD in a normal patient with a balanced Robertsonian 14:14 translocation and a history of multiple miscarriages. Five previous reports of chromosome 14 UPD suggest that an adverse developmental effect may be more severe whenever the UPD is paternal in origin. This is the second reported patient with paternal UPD and the fifth reported with maternal UPD, and only few phenotypic similarities are apparent. Examination of these chromosome 14 UPD cases of maternal and paternal origin suggests that there are syndromic imprinting effects.

NF1 mutation analysis using a combined heteroduplex/SSCP approach

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder characterized predominantly by neurofibromas, café‐au‐lait spots, and Lisch nodules. The disease is caused by disruptive mutations of the large NF1 gene, with half of cases caused by new mutation. Less than 100 constitutional mutations have thus far been published, ranging from very large deletions to point mutations. We have pursued NF1 mutation analysis by heteroduplex analysis (HDA) and single‐strand conformational polymorphism analysis (SSCP) of individual exons. We streamlined these techniques to eliminate the use of radioactivity, to apply both methods to the same PCR product, and to multiplex samples in gels. Applied simultaneously to a set of 67 unrelated NF1 patients, HDA and SSCP have thus far identified 26 mutations and/or variants in 45 of the 59 exons tested. Disease‐causing mutations were found in 19% (13/67) of cases studied. Both techniques detected a variety of mutations including splice mutations, insertions, deletions, and point changes, with some overlap in the ability of each method to detect variants. Hum Mutat 9:548–554, 1997.

Peripheral neuropathy in Ehlers-Danlos syndrome

Two unrelated male patients with clinical manifestations of Ehlers-Danlos syndrome type III and peripheral neuropathy are presented. At age 13 years, one developed bilateral brachial plexus palsy unrelated to trauma and 2 years later, a right lumbosacral plexopathy. The other presented at age 3 years with a left brachial plexopathy after sustaining a fracture of the lateral condyle of the right humerus. In both patients, nerve conduction velocities demonstrated conduction block across the brachial plexus and recovery was incomplete, indicating that peripheral neuropathy is a serious complication of Ehlers-Danlos syndrome. Its prompt diagnosis facilitates the care of patients with this syndrome. Increased ligament laxity/stretchability and mechanical trauma may play an important role in the pathogenesis of the neuropathy.

Tracheoesophageal anomalies in oculoauriculovertebral (Goldenhar) spectrum

Tracheoesophageal fistula, with or without esophageal atresia (TEF/EA) appears to be a defect of blastogenesis, as is the oculoauriculovertebral (Goldenhar) spectrum (OAVS), with which it has occasionally been associated. We reviewed the records of all OAVS patients evaluated through the University of South Florida Regional Genetics Program between 1985 and 1993. Of 60 OAVS patients, three had TEF/EA. These results suggest that TEF/EA in association with OAVS is underreported. The occurrence of TEF/EA should prompt a thorough search for other known anomalies of OAVS.

Expanded phenotype of cranioectodermal dysplasia (Sensenbrenner syndrome)

Cranioectodermal dysplasia (CED) is an autosomal recessive condition characterized by defects of ectoderm-derived structures and characteristic bone anomalies. We report on a 27-month-old Caucasian girl with CED, pre- and postnatal growth retardation, microcephaly, hypoplasia of the posterior corpus callosum, photophobia, and aberrant calcium homeostasis. Since new traits were encountered, we reviewed all reported patients and one unpublished case and compared the frequency rates of the individual manifestations. The findings present in all patients are dolichocephaly and rhizomelia. Ectodermal dysplasia manifestations are variable. Short thorax and heart defect are inconsistent. Previously unreported anomalies include growth deficiency, delayed psychomotor development, microcephaly, photophobia, and abnormal calcium homeostasis. These clinical manifestations may facilitate the diagnosis of this condition.

Sipple syndrome with lichen amyloidosis as a paracrinopathy: Pleiotropy, heterogeneity, or a contiguous gene?

A five-generation white family with multiple endocrine neoplasia type 2A had six affected members. Two, a mother and her daughter, had interscapular cutaneous pruritic lesions resembling macular/lichen amyloidosis. In the daughter, light microscopy showed homogeneous aggregates in the papillary dermis. Crystal violet staining showed metachromasia and indicated that the deposits were amyloid. This is the fourth family with familial medullary thyroid carcinoma with cutaneous amyloidosis and as such it allowed comparative analysis. Genetic heterogeneity, a contiguous gene, and pleiotropy were considered. It appears that multiple endocrine neoplasia type 2A/familial medullary thyroid carcinoma with cutaneous amyloidosis represents the phenotypic variability of the expression of a pleiotropic gene. The condition is one of the predominantly ectodermal autosomal dominant phakomatoses and is most likely a paracrinopathy.

Cryptorchidism in Mental Retardation

We surveyed 148 institutionalized male subjects to study the prevalence of cryptorchidism among mentally retarded individuals. Of the patients 121 (81.7 per cent) were profoundly (intelligence quotient 19 or less), 21 severely (20 to 35), 5 moderately (36 to 51) and 1 mildly (65) retarded. Patient age ranged from 1 to 36 years (mean 13.6 means). According to the etiology of the mental retardation the cases were classified into 6 categories: chromosomal aberrations, single gene disorders, polygenic conditions, teratogen-induced anomalies, perinatal/postnatal injuries and idiopathic mental retardation. Cryptorchidism was found in 44 individuals (39.7 per cent), and was bilateral 3.4 times more often than unilateral. Cerebral palsy occurred in 88 patients. There were 36 patients with cryptorchidism and cerebral palsy, representing 41 per cent of the patients with cerebral palsy and 81.8 per cent of the cryptorchid group (p equals 0.0006). Among the noncryptorchid male subjects 52 (50 per cent) had cerebral palsy. Epilepsy also was more frequent in the cryptorchid group (p equals 0.0333). The cryptorchid and noncryptorchid groups did not show a significant difference in the etiology of mental retardation except in the perinatal/postnatal category in which cryptorchidism was more frequent (p equals 0.025), and in the polygenic category in which all 9 patients were noncryptorchid. This study shows a high prevalence of cryptorchidism in individuals with profound and severe mental retardation, and particularly in those having cerebral palsy.

Angioid Streaks Associated with Hereditary Spherocytosis

We examined members of a family in whom hereditary spherocytosis had appeared in three generations. Angioid streaks were confirmed in the second generation and presumed to exist in the first generation. A woman in the third generation with hereditary spherocytosis did not have angioid streaks but these are age-related and may develop later. The one individual in the second generation without hereditary spherocytosis did not have angioid streaks. Angioid streaks associated with hereditary spherocytosis in this family did not appear to be coincidental. Patients with hereditary spherocytosis should be examined for angioid streaks because of the implications for their vision.

The phakomatoses as paracrine growth disorders (paracrinopathies)

A microcomputer database management system retrieved all 170 probands with phakomatoses evaluated through the genetic clinics at the University of South Florida between January 2, 1982 and December 31, 1987. Neurofibromatosis (NF) was the diagnosis of 118 of them; 42 had other phakomatoses and 10 had transitional phenotypes difficult to classify. The analysis of the hamartomas of all probands indicated disorganized differentiation and overgrowth of cell species characteristic for the involved tissue and location. Abundance of extracellular fibrillary components was also evident in most hamartomas. Adequate blood suppy was a conditio sine qua non. This was seen in monogenic, sporadic, transitional and combined phakomatoses alike and implied a common pathogenesis. The paracrine growth factors and their regulation emerged as the most plausible common denominator for the pathogenesis. A unitary pathogenetic hypothesis is proposed that the phakomatoses represent paracrine growth regulation disorders (paracrinopathies). Conditions such as fibromatoses, lipomatoses, lipody‐strophies, hemihyper/hypotrophies, including Russell‐Silver and Beckwith‐Wiedemann syndromes may be proven to be paracrinopathies as well.

Chromosome 3p25 deletion in mother and daughter with minimal phenotypic effect

3p25 deletion syndrome is characterized by mental retardation, growth retardation, hypotonia, microcephaly, ptosis, and micrognathia. Of the 42 persons with this deletion syndrome cited in the literature, only 2 patients, a mother–daughter pair, have previously been reported without apparent clinical consequence. We present a second mother–daughter dyad with a terminal 3p25.3–3pter deletion, who present with only mild clinical effects. In addition to cytogenetic analysis, array CGH was performed to determine the breakpoints at the molecular level. Our data show that the 3p25 deletion syndrome may, therefore, reflect a much broader phenotypic spectrum than previously recognized.