Duane W. Superneau

Neurofibromatosis 2: Clinical and DNA Linkage Studies of a Large Kindred

At least eight provisional categories of neurofibromatosis have been proposed. Among these, neurofibromatosis 1 (von Recklinghausens disease or peripheral neurofibromatosis) and neurofibromatosis 2 (central or bilateral acoustic neurofibromatosis) have been established as distinct disorders. We studied 15 affected male and 8 affected female members of one large kindred with neurofibromatosis 2. None of the patients met the diagnostic criteria for neurofibromatosis 1. Between the ages of 15 and 53 years, the patients had multiple central nervous system tumors of various types--mainly, bilateral acoustic neuromas. Two or more tumors eventually developed in 20 of the patients; 9 had evidence of only bilateral acoustic neuromas. Meningiomas and ependymomas were more common among the young patients; those who initially presented with acoustic neuromas were nearly a decade older. Intracranial nontumoral calcifications were present in most patients and were also found in symptom-free children. The presence of such lesions is probably a prodromic feature of neurofibromatosis 2. Simultaneous analysis of D22S1 and IGLV DNA markers for coinheritance with neurofibromatosis 2 indicates that the locus for the disease is near the center of the long arm of chromosome 22 (22q11.1----22q13.1). The eventual isolation of this disease gene may reveal a cause of the most common intracranial tumors in humans.

Myopathy in Marinesco-Sjogren Syndrome

Progressive muscular weakness, hypotonia and atrophy are among the cardinal signs of the Marinesco-Sjogren syndrome but have not been extensively investigated. Our study focused on 6 related patients who are members of an inbred population. Muscle biopsies revealed myopathic alterations with variation of fiber size, rounding, degeneration and regeneration of fibers, internalization of nuclei and endomysial fat and fibrosis. Most patients had elevated serum creatine kinase levels. One patient revealed endstage neuromuscular disease and had normal serum creatine kinase levels. Of particular interest was the finding of conspicuous myopathy in 2 young children. Thus far, it has not been appreciated that myopathy represents an early sign of the Marinesco-Sjogren syndrome.

Severe end of Opitz trigonocephaly (C) syndrome or new syndrome

We report on four unrelated cases of an Opitz trigonocephaly (C)-like syndrome with a highly characteristic combination of facial anomalies including prominent metopic suture, exophthalmos, hypertelorism, cleft lip and palate, flexion deformities of the upper limbs and multiple other anomalies. We also review two very similar published cases formerly considered to have the C syndrome. Although there is overlap, a clinical distinction from the Opitz trigonocephaly and other syndromes seems possible, and thus a specific causal entity may be postulated.

FG syndrome: Report of three new families with linkage to xq12-q22.1

FG syndrome is a rare X-linked recessive form of mental retardation, first described by Opitz and Kaveggia in 1974 in five related males with mental retardation, disproportionately large heads, imperforate anus, and congenital hypotonia. Partial agenesis of the corpus callosum was noted in at least one of the initial cases and has been seen in a number of subsequently-reported cases. The associated congenital hypotonia with joint hyperlaxity tends to progress to contractures with spasticity and unsteady gait in later life. The presence of subtle facial abnormalities and the characteristic behavior in midchildhood facilitate diagnosis at this age, particularly when there are other affected male relatives in the maternal family. Recently, Briault et al. [1997] mapped a gene for FG syndrome to the Xq12-q21.31 region. We describe three additional families (six additional patients) with FG syndrome on whom we have conducted linkage analysis. Our findings support the localization of a gene for the FG syndrome in Xq12-q21. In addition, we have noted skewed X-inactivation in carrier females, as well as new associated findings in affected males of sagittal craniosynostosis and split hand malformation.

Clinical and behavioral characteristics in FG syndrome

FG syndrome is a rare X-linked recessive form of mental retardation, first described by Opitz and Kaveggia in 1974. Based on over 50 reported cases, FG syndrome is associated with agenesis of the corpus callosum, minor facial anomalies (high, broad forehead with frontal cowlick, ocular hypertelorism, down-slanted palpebral fissures, and small cupped auricles), relative macrocephaly, broad thumbs and halluces, and prominent fetal fingertip pads. Affected individuals manifest neonatal hypotonia and severe constipation, which usually resolves during mid-childhood. The hypotonia with joint hyperlaxity evolves into spasticity with joint contractures in later life. Affability, hyperactivity, and excessive talkativeness are noted frequently in patients with FG syndrome. Recently, we described three additional families (six additional patients) with FG syndrome who support the localization of a gene for the FG syndrome in chromosome region Xq12-q21 [Graham JM Jr, Tackels D, Dibbern K, Superneau D, Rodgers C, Corning K, Schwartz CE. 1998. Am J Med Genet 80:145-156.]. Using these same families and one additional sporadic case of FG syndrome, we compared behavioral and personality characteristics of 6 FG boys with other boys with syndromic and nonsyndromic mental retardation: eight with Down syndrome, seven with Prader-Willi syndrome, eight with nonspecific mental retardation, and 13 with Williams syndrome. Using the Vineland Adaptive Behavior Scales, the Reiss Personality Profiles, and the Achenbach Child Behavior Checklist, parents were asked to characterize the behavior and personality of their boys from ages 4 to 10 years. When compared with Williams syndrome, the FG boys had fewer internalizing behaviors and were significantly less anxious and withdrawn but had similar socially oriented, attention-seeking behaviors. On the Reiss Profile, FG boys were also quite similar to Williams syndrome boys. On the Vineland Scales, FG boys demonstrated significant relative strengths in their socialization skills, consistent with their personality, tending to confirm previous descriptions of their personalities.

Fertility and the cri du chat syndrome

We describe a mother and daughter with typical cri du chat syndrome. Previous investigators have noted the lack of information about the reproductive fitness of patients with this disorder. This report demonstrates that females with cri du chat syndrome are fertile, can gestate and likewise deliver affected offspring, which has significant management and counseling implications.

NEUROFIBROMATOSIS II (ACOUSTIC NEUROMA-MENINGIOMA)

Neurofibromatosis (NF) has been categorized as type I (von Recklinghausen) or type II (formerly “Central NF”), and other categories have been proposed (III-VII).Our investigations concern a large kindred with NF II that spans 7 generations and includes over 300 members. Affected individuals do not fulfill the diagnostic criteria of NF I. Their symptoms and signs are direct byproducts of the emergence of nervous system neoplasia. Clinical and histologic data from 28 patients (14 males, 14 females) indicate that the most prevalent neoplasms are acoustic neuromas (AN) (15 cases) followed by meningiomas (MEN) (8 cases) and ependymomas (2 cases). MEN, if present, are diagnosed during puberty or shortly after (earliest onset 16 years) and tend to be multiple. Individuals developing symptoms later (latest onset 6th decade) tend to be free of MEN, and instead develop AN which most often are bilateral. None of the affected developed optic glioma or pheochromocytoma.Molecular studies of MEN and AN tissue were indicative of a loss of genes on chromosome 22 (Seizinger et al, 1986), a strong clue to the chromosomal location of the defect. Molecular studies of this kindred by the same investigators are in process to determine whether the NP II gene is on chromosome 22.

MYOPATHY (SKELETAL AND CARDIAC) AND WHISTLING-FACE SYNDROME (WF)

Diagnosis of the Whistling-Face syndrome (WF) usually follows the observation of microstomia and a stigmatic facies associated with ulnar deviation of fingers and joint contractures. Muscle atrophy and myopathy, although reported in WF, receive insufficient emphasis. More recently, cardiomyopathy and malignant hyperthermia have been observed in WF patients. Our clinical studies and review bring support to the conclusion that the spectrum of WF includes; skeletal weakness, hypertrophic cardiomegaly with WPW conduction abnormalities (unresponsive to quinidine), and elevated serum CPK, GOT, and LDH. Hypertrophic cardiomyopathy with enlarged myofilaments due to abundant amyloid-like material, and skeletal myopathy with scattered fiber atrophy and focal areas of fatty deposition and myelin fibers, are also part of WF.Consequently, individuals with primary hypertrophic cardiomyopathy or a history of malignant hyperthermia should also be assessed for clinical features of WF and vice versa. Because WF presents with clinical variability and is an autosomal dominant disorder of prenatal onset, a family history of any of the features described above may be pertinent in genetic counseling and prenatal assessment of families with WF syndrome.