Phenotypic expansion and further characterisation of the 17q21.31 microdeletion syndrome.

BACKGROUND: The recognition of the 17q21.31 microdeletion syndrome has been facilitated by high resolution microarray technology. Recent clinical delineation of this condition emphasises a typical facial appearance, cardiac and renal defects, and speech delay in addition to intellectual disability, hypotonia and seizures. METHODS AND RESULTS: We describe 11 previously unreported patients expanding the phenotypic spectrum to include aortic root dilatation, recurrent joint subluxation, conductive hearing loss due to chronic otitis media, dental anomalies, and persistence of fetal fingertip pads. Molecular analysis of the deletions demonstrates a critical region spanning 440 kb involving either partially or wholly five genes, CRHR1, IMP5, MAPT, STH, and KIAA1267. CONCLUSION: These data have significant implications for the clinical diagnosis and management of other individuals with 17q21.31 deletions.

Rett syndrome: natural history and management.

The clinical findings of seven girls and one woman, 2 to 25 years of age, with Rett syndrome are presented. Previous diagnoses included Prader-Willi syndrome, Angleman syndrome, toxic reaction to pertussis vaccine, CNS dysgenesis, and encephalitis. Rett syndrome has a recognizable neurodevelopmental phenotype without a specific biologic marker, which makes the diagnosis difficult at times. Treatment is largely supportive, and an active parents' association has been helpful to many families.

Johanson-Blizzard syndrome with normal intelligence.

We report a brother and sister with apparent Johanson-Blizzard syndrome and normal intelligence. There is a wide range of intellectual abilities of persons with Johanson-Blizzard syndrome. No phenotypic predictors of ultimate intellectual function were found in the literature.

Mild Brachmann-de Lange syndrome. Phenotypic and developmental characteristics of mildly affected individuals.

Since 1981, we have identified 3 patients with mild Brachmann-de Lange syndrome (BDLS) who have had subtle but definite manifestations of the syndrome and mild effects on growth and development. J.G. (B.D. 12/9/72) was first examined at 20 months. He had rather typical craniofacial findings and hirsutism, limitation of full supination of his arms, and brachyclinodactyly of the 5th fingers. IQ was estimated at 65. K.H. (B.D. 10/10/83) was first examined by us at age 9 months and was diagnosed as having "mild" BDLS. At age 5, K.H. has demonstrated relatively normal cognitive development (low average-average IQ of 74) with specific learning problems: weakness of visual-motor skills, delayed expressive language development, and articulation difficulties. At age 7, he was attending a regular 1st grade classroom, with some special education assistance. M.E. (B.D. 4/19/78) was diagnosed at age 10 years as having "mild" BDLS. His physical changes were more subtle than those of the 2 patients above. At age 10, M.E. was in the regular 4th grade classroom receiving special education support. His IQ was in the borderline-low-average range. He had strengths in rote verbal skills, with weaknesses in reading and writing. These 3 patients demonstrate mild BDLS in which characteristic manifestations of the syndrome, particularly craniofacial anomalies, are present and recognizable, but quite subtle, thus making the clinical diagnosis difficult. In addition, the milder physical phenotype is associated with milder cognitive and behavioral consequences.(ABSTRACT TRUNCATED AT 250 WORDS)

Longitudinal observations on 15 children with Wiedemann-Beckwith syndrome.

We conducted a follow-up study on 15 patients with Wiedemann-Beckwith syndrome (WBS) to further clarify major and minor diagnostic clinical characteristics and longterm expectations for growth and development. We found patients with WBS tended to have polyhydramnios with large placentas which were almost twice normal placental weight. The large fetal size and polyhydramnios often resulted in early delivery with occasional perinatal mortality (three cases). Increased placental size, with associated polyhydramnios resulting in excessive umbilical cord length, may be useful in suspecting WBS prior to delivery, thereby facilitating perinatal management. The presence of abdominal wall defects and/or macroglossia may help to confirm the diagnosis. At birth, patients were almost 2 standard deviations above the expected mean for gestational age, length, and weight. This trend continued through early childhood and then excessive size became less dramatic with increasing age. We detected no cytogenetic variations in nine patients who had studies done and, to date, no tumors have been detected other than a gastric teratoma that was evident in one infant at birth. Longitudinally, the children have not had an unusual incidence of medical problems, and long-term ultrasound monitoring was not burdensome to the families. In comparison, mental and social development to unaffected siblings and cousins appeared normal.

Smith-Magenis syndrome resulting from a de novo direct insertion of proximal 17q into 17p11.2.

We report on a de novo intrachromosomal rearrangement of chromosome 17 in a patient with Smith-Magenis syndrome (SMS). This 11-year-old boy had short stature, midfacial hypoplasia, and behavioral problems characteristic of this syndrome. Cytogenetic analysis showed that the proximal long arm of a chromosome 17 (q11.2-q21.3) was inserted into its short arm at p11.2, resulting in an apparent deletion of the SMS critical region [ins(17)(p11.2q11.2q21.3)]. Fluorescence in situ hybridization studies (FISH) demonstrated that the inserted segment included both the ERBB2 and RARA loci, and dual color hybridizations defined the insertion as direct, with ERBB2 located more proximally on the short arm of the der(17). The resulting deletion of the short arm included loci c130G3, D17S258, FLI, and D17S29, while the more proximal loci, D17S446 and D17S58, remained apparently unaffected and in their native locations. The CMT1A locus also remained in its native location on the short arm of the metacentric der(17) chromosome. A de novo intrachromosomal insertional rearrangement of chromosome 17 in a case of SMS has not been reported previously and further illustrates the instability of this chromosomal region.

The Johanson-Blizzard syndrome: a second report of full autopsy findings.

We report on a second patient with Johanson-Blizzard syndrome with full autopsy. The findings are similar to those of the one other available case, but gross or fine CNS maldevelopment was not present; although small by weight, the brain showed no cytoarchitectural disturbance. Normal intellectual development does occur in this syndrome and may relate to the variable effects of the deleterious gene on the developing CNS.

Acrocallosal syndrome: new findings.

We describe a 21-month-old girl with typical manifestations of the acrocallosal syndrome of craniofacial anomalies, agenesis of the corpus callosum, hallucal duplication, severe hypotonia, and psychomotor retardation. Our patient also had the Dandy-Walker malformation, imperforate anus with rectovaginal fistula, hypothalamic dysfunction with hypothyroidism and diabetes insipidus, thick, dysplastic pulmonic valve leaflets, central and obstructive apnea, and pulmonary hypertension. These findings add to the delineation of this syndrome.

Radiological features in Brachmann-de Lange syndrome.

Brachmann-de Lange syndrome (BDLS) is a well-delineated disorder consisting variably of pre- and postnatal growth deficiency, microbrachycephaly, characteristic face, hypertrichosis, visceral anomalies, and limb defects consisting primarily of variable limb reduction defects, micromelia, and elbow abnormalities. The course is usually marked by initial hypertonicity, low-pitched weak cry, feeding problems, and behavioral problems with marked mental deficiency. In classical cases there is rarely any difficulty in making the diagnosis, but for mildly affected cases, it may be difficult to feel secure about the diagnosis. In an effort to increase the precision of diagnosis for mildly affected cases, we reviewed roentgenograms in 21 cases of Brachmann-de Lange syndrome, as well as previously published descriptions of the radiological manifestations. Unusual radiologic manifestations were related primarily to the limb anomalies, and these were often asymmetric. These manifestations included digital abnormalities, which ranged from acheiria to oligodactyly, hypoplasia of the thumb and first metacarpal, clinodactyly of the fifth finger, or ectrodactyly. Long bone abnormalities included ulnar a/hypoplasia, dysplasia of the radial head, or fusion of the elbow. When there was a single forearm bone, there was often fusion at the elbow and oligodactyly, which made it difficult to determine whether the radius or ulna was absent. Other radiologic manifestations included 13 ribs with precocious sternal fusion, and micrognathia. We suggest that these radiologic manifestations could increase diagnostic precision in mildly affected cases.

Familial t(11;13)(q21;q14) and the duplication 11q, 13q phenotype.

Cases of duplication of distal 11q or proximal 13q have been reported independently. A specific translocation resulting in duplication of distal 11q, [der(22)t(11;22)(q23;q11)], has been documented in over 40 cases. We report on a male fetus with chromosomal excess of both distal 11q and proximal 13q resulting from a familial translocation. This case supports the causal association of duplication 11q with neural tube defects.

Familial translocation 5;14 resulting in an unbalanced offspring.

We report on an infant with multiple congenital anomalies possessing a derivative 14 chromosome in excess of the normal complement, resulting from transmission of a familial t(5;14)(p13;q22). The proposita's phenotypically normal mother, mentally retarded half-brother, and fetal sib are carriers of the apparently balanced translocation. Previous cases of similar familial t(5;14) are reviewed. The proposita's phenotype is characterized by failure to thrive, developmental retardation, cleft palate, congenital heart anomaly, abnormal hands and feet, unusual face with abnormal ears, and recurrent respiratory infections. The proposita died at age 9 months and postmortem examination showed multiple central nervous system, cardiopulmonary, gastrointestinal, and genital malformations. Our proposita's phenotype is attributable to contributions from both chromosomes and is consistent with the consequences of both the dup(5p) and dup(14q).

Maternal disomy and Prader-Willi syndrome consistent with gamete complementation in a case of familial translocation (3;15) (p25;q11.2).

Maternal uniparental disomy (UPD) for chromosome 15 is responsible for an estimated 30% of cases of Prader-Willi syndrome (PWS). We report on an unusual case of maternal disomy 15 in PWS that is most consistent with adjacent-1 segregation of a paternal t(3;15)(p25;q11.2) with simultaneous maternal meiotic nondisjunction for chromosome 15. The patient (J.B.), a 17-year-old white male with PWS, was found to have 47 chromosomes with a supernumerary, paternal der(15) consisting of the short arm and the proximal long arm of chromosome 15, and distal chromosome arm 3p. The t(3;15) was present in the balanced state in the patient's father and a sister. Fluorescent in situ hybridization analysis demonstrated that the PWS critical region resided on the derivative chromosome 3 and that there was no deletion of the PWS region on the normal pair of 15s present in J.B. Methylation analysis at exon alpha of the small nuclear ribonucleoprotein-associated polypeptide N (SNRPN) gene showed a pattern characteristic of only the maternal chromosome 15 in J.B. Maternal disomy was confirmed by polymerase chain reaction analysis of microsatellite repeats at the gamma-aminobutyric acid receptor beta3 subunit (GABRB3) locus. A niece (B.B.) with 45 chromosomes and the derivative 3 but without the der(15) demonstrated a phenotype consistent with that reported for haploinsufficiency of distal 3 p. Uniparental disomy associated with unbalanced segregation of non-Robertsonian translocations has been reported previously but has not, to our knowledge, been observed in a case of PWS. Furthermore, our findings are best interpreted as true gamete complementation resulting in maternal UPD 15 and PWS.

Paternally derived de novo interstitial duplication of proximal 15q in a patient with developmental delay.

Interstitial duplications of proximal 15q containing the Prader-Willi syndrome/Angelman syndrome (PWS/AS) region have been found in patients with autism or atypical autism. In these cases with an abnormal phenotype, the duplications were maternally derived. Paternal origin of the duplication has been associated with a normal phenotype. We report on a patient who presented with nonspecific developmental delay and partial agenesis of the rostral corpus callosum. Fluorescence in situ hybridization (FISH) studies using probes specific for the PWS/AS region demonstrated a double signal on one chromosome 15, indicating the presence of an interstitial duplication of proximal 15q involving the PWS/ AS region in the patient. Parental chromosomes were normal with FISH studies. Methylation analysis at exon alpha of the SNRPN locus showed a maternal band at 4.2 kb and a paternal band of apparent double intensity at 0.9 kb, suggestive of one copy of the maternal allele and two copies of the paternal allele in the patient. Microsatellite analysis was informative at the GABRB3 locus in the family, which showed the inheritance of two different paternal alleles and a maternal allele in the patient consistent with the origin of this duplication from an unequal crossing over between the two chromosome 15 homologs in the father. This is the first report of an abnormal phenotype associated with a paternally derived duplication of proximal 15q shown to contain the PWS/AS region by molecular techniques.

Evidence report: Genetic and metabolic testing on children with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.

OBJECTIVE: To systematically review the evidence concerning the diagnostic yield of genetic and metabolic evaluation of children with global developmental delay or intellectual disability (GDD/ID). METHODS: Relevant literature was reviewed, abstracted, and classified according to the 4-tiered American Academy of Neurology classification of evidence scheme. RESULTS AND CONCLUSIONS: In patients with GDD/ID, microarray testing is diagnostic on average in 7.8% (Class III), G-banded karyotyping is abnormal in at least 4% (Class II and III), and subtelomeric fluorescence in situ hybridization is positive in 3.5% (Class I, II, and III). Testing for X-linked ID genes has a yield of up to 42% in males with an appropriate family history (Class III). FMR1 testing shows full expansion in at least 2% of patients with mild to moderate GDD/ID (Class II and III), and MeCP2 testing is diagnostic in 1.5% of females with moderate to severe GDD/ID (Class III). Tests for metabolic disorders have a yield of up to 5%, and tests for congenital disorders of glycosylation and cerebral creatine disorders have yields of up to 2.8% (Class III). Several genetic and metabolic screening tests have been shown to have a better than 1% diagnostic yield in selected populations of children with GDD/ID. These values should be among the many factors considered in planning the laboratory evaluation of such children.

Cognitive functioning in the fragile-X syndrome: a study of intellectual, memory and communication skills.

There may be several cognitive features that characterize fragile-X syndrome in both males and females. Since this study is one of the few that examines noninstitutionalized individuals with the syndrome, future studies of affected individuals should continue to include formal assessment of their cognitive skills. Likewise, the examination in this study of one single family with fragile-X syndrome indicates that further evaluation of verbal, perceptual, memory, language and speech skills is necessary to determine the prevalence of the features described.

A case of de novo translocation 7; 10 and the duplication 7p, deletion 10p phenotype.

A patient with a de novo duplication of 7pter-->7p12 and deletion of distal 10p resulting from an unbalanced translocation is described. The patient's phenotype demonstrates features associated with other reported cases with similar imbalances which include hypertelorism, Dandy-Walker malformations, ventricular septal defect, bilateral cleft lip and palate, abnormal hand positions and clubbed feet, hypospadias, and imperforate anus.

Schizophrenia and mental retardation in an adult male with a de novo interstitial deletion 9(q32q34.1).

A 28 year old man with mental retardation and therapeutically controlled schizophrenia was found to have a de novo interstitial deletion in the long arm of a chromosome 9 (46,XY,del(9)(q32q34.1). Additional phenotypic abnormalities included short stature, a short webbed neck with a low posterior hairline, dysmorphic facies, a narrow palate with an inverted V soft palate, and tapered fingers with bilateral short fifth metacarpals. Interstitial deletion of chromosome 9 is a rare finding and we are aware of only one other case involving the q32q34.1 region.

Autosomal dominant familial spastic paraplegia: description of a large New England family and a study of management.

A large New England family with autosomal dominant familial spastic paraplegia (ADFSP) is described. In a pedigree of 173 family members, 71 affected individuals were identified. 16 cases examined by the authors are described with regard to the natural history of ADFSP in this family, and a staging system for following progress and planning interventions is proposed. Three illustrative cases are presented. In this family, ADFSP was found to have a homogeneous clinical course, with nearly complete penetrance. Onset, with involvement limited to the lower extremities, occurred by three years of age, after which no significant progression was noted. Early, aggressive habilitative care may result in more functional ambulation for the youngest family members.