KBG syndrome: report of twins, neurological characteristics, and delineation of diagnostic criteria

KBG syndrome is a multiple congenital anomaly (MCA) syndrome comprising developmental delay, postnatal short stature, and delayed bone age. Many physical anomalies involving the face, hands, and costovertebral axis have been described in this syndrome. We present twin males with KBG syndrome and a review of 50 published case reports, with particular emphasis on the neurological aspects of KBG syndrome, including seizures, MRI findings, and behavior difficulties. It is argued that diagnostic criteria for KBG syndrome should include neurological involvement, that is, global developmental delay, seizures, and/or mental retardation (MR). The characteristic facial changes and representative hand and costovertebral anomalies are also defined. These diagnostic criteria were obtained from 50 publications and appeared to support the diagnosis in 43 cases. They will be helpful to pediatricians, geneticists, and neurologists in evaluating patients for this condition.     

Thrombocytopenia-absent radius syndrome: a clinical genetic study

The thrombocytopenia-absent radius (TAR) syndrome is a congenital malformation syndrome characterised by bilateral absence of the radii and a thrombocytopenia. The lower limbs, gastrointestinal, cardiovascular, and other systems may also be involved. Shaw and Oliver in 1959 were the first to describe this condition, but it was Hall et al in 1969 who reported the first major series of patients. Since then most reports have been based on single or small numbers of cases. We report the results of a clinical study looking at the phenotype of 34 patients with TAR syndrome. All cases had a documented thrombocytopenia and bilateral radial aplasia, 47% had lower limb anomalies, 47% cow's milk intolerance, 23% renal anomalies, and 15% cardiac anomalies. Congenital anomalies not previously described in association with TAR syndrome included facial capillary haemangiomata, intracranial vascular malformation, sensorineural hearing loss, and scoliosis. Karyotype analysis, chromosome breakage studies including premature centromeric separation and fluorescence in situ hybridisation studies looking for a deletion of chromosome 22q11 were undertaken. Two abnormal karyotypes were identified.     

Bilateral polymicrogyria as the indicative feature in a child with a 22q11.2 deletion

Polymicrogyria (PMG) is a brain malformation due to abnormal cortical organisation. It is a heterogeneous disorder associated with 22q11.2 deletion syndrome (also known as velocardiofacial (VCF) syndrome) amongst others. Since this association was first recognised in 1996, over 30 patients with PMG and 22q11.2 deletion have been described. In 22q11.2 deletion syndrome, PMG is mainly located in the perisylvian areas; it frequently has an asymmetrical presentation with a striking predisposition for the right hemisphere. Neurological features of perisylvian PMG include developmental delay/mental retardation, seizures, microcephaly, spasticity and oromotor dysfunction. Thus in children diagnosed with 22q11.2 deletion syndrome, a finding of PMG has important prognostic value. We present a seven-month old boy with microcephaly, short stature and developmental delay. A cerebral MRI showed slightly enlarged ventricles and symmetrical perisylvian polymicrogyria. A 22q11.2 deletion was revealed by array-based comparative genomic hybridization. Remarkably the boy had no other manifestations of VCF syndrome. Paediatricians, child neurologists and clinical geneticists should be aware that the presence of PMG (especially in the perisylvian areas) needs investigating for 22q11.2 deletion, even if other more common VCF syndrome features are absent.     

Nephrotic syndrome, microcephaly, and developmental delay: three separate syndromes

We describe a patient with microcephaly, developmental delay, and nephrotic syndrome who had normal renal function and normal brain imaging studies. She does not have the Galloway-Mowat syndrome. The concurrence of nephrotic syndrome with microcephaly and developmental delay may be coincidental, or may reflect one of at least three syndromes: Galloway-Mowat, a second syndrome of microcephaly, nephrotic syndrome and developmental delay (MNSDD), and a third syndrome of microcephaly, developmental delay, and spondylorhizomelic short stature.     

Type IV Ehlers-Danlos syndrome presenting as sudden infant death

A previously healthy 5-month-old female infant presented with sudden death due to spontaneous subarachnoid hemorrhage associated with minor multifocal visceral hemorrhages. The clinical diagnosis had been sudden infant death syndrome. Although the family history was noncontributory and other features of type IV Ehlers-Danlos syndrome (EDS) were absent, the pattern of hemorrhage was consistent with this type of connective tissue disorder. The diagnosis was confirmed after postmortem analysis of skin and aorta showed less than 5% type III collagen (normal greater than 15%). Extensive literature review failed to find any other reported cases of sudden death in infancy due to intracranial hemorrhage in patients with previously unsuspected type IV EDS. The authors suggest that collagen analysis should be performed in cases of unexplained multifocal spontaneous hemorrhage in infancy so that this rare diagnosis will not be missed.     

Study of 250 children with idiopathic mental retardation reveals nine cryptic and diverse subtelomeric chromosome anomalies

Cryptic subtelomeric chromosome anomalies have been recognized as a significant cause of dysmorphology and mental retardation. To determine whether the clinical cytogenetics laboratory should screen routinely for these aberrations, we have tested 250 patients with idiopathic mental retardation/developmental delay, either isolated (53) or associated with dysmorphic features and/or malformations in the absence of a recognizable syndrome (197). All had normal karyotypes at the 550-850 band level. Subtelomeric anomalies were found in 1/53 of the first group (1.9%) and 8/197 of the second group (4.1%). In one patient, two separate anomalies were present: a deletion (not inherited) and a duplication (inherited). It is possible that one of these 10 observed aberrations might represent a rare and previously unreported polymorphism and one a rare cross-hybridization. Our study supports the proposition that cryptic subtelomeric rearrangements are a significant cause of idiopathic mental retardation/developmental delay, but both the diversity of the phenotypes of the positive cases and the wide diversity of their associated chromosome abnormalities emphasize the central problem for the clinical cytogenetics laboratory-that of choosing the most productive patient base for this useful diagnostic test.     

Syndrome of congenital cataracts, sensorineural deafness, Down syndrome-like facial appearance, short stature, and mental retardation: two additional cases

An apparently new syndrome of congenital cataracts, sensorineural deafness, Down syndrome-like facial appearance, short stature, and mental retardation was described by Gripp et al. 1996. The authors reported on two unrelated patients with congenital cataracts, sensorineural deafness, distinctive facial appearance, mental retardation, postnatal short stature, and skeletal changes. We report on two additional patients with findings most similar to the reported patients by Gripp et al. 1996, including bilateral congenital cataracts, hearing loss, craniofacial abnormalities, short stature, skeletal abnormalities, and developmental delay. Both of the patients reported herein had chromosome microarray analysis, which showed normal results in Patient 2 but abnormal results in Patient 1 and his mother who both had a chromosome 11q25 subtelomere deletion. Patient 1 and his mother's findings are atypical for the common findings reported in Jacobsen syndrome (11q terminal deletion syndrome), and consistent with the patients reported by Gripp et al. 1996. The etiology for these cases has been unknown. The microarray results on Patient 1 suggest that the other patients with findings of developmental delay, short stature, congenital cataracts, sensorineural hearing loss, and similar craniofacial features may have either a microdeletion of chromosome 11q terminal region or haploinsufficiency of a gene localized to this region.     

Thrombocytopenia with absent radius in a boy and his uncle

We report a boy and his maternal uncle who have Thrombocytopenia-Absent Radius (TAR) syndrome. The mother of the propositus is normal. A maternal aunt has mild radial hypoplasia, possibly representing partial expression of the syndrome. A review of the literature shows several pedigrees in which relatives other than sibs were affected with TAR. Thus, autosomal recessive inheritance may not account for all cases and alternate modes of transmission should be considered.     

Yellow teeth, seizures, and mental retardation: a less severe case of Kohlschütter-Tönz syndrome

We describe an 11-year-old boy with hypoplastic amelogenesis imperfecta, yellow teeth, seizures, and developmental delay, which are the hallmarks of Kohlschütter-T?nz syndrome. Compared to other reported cases of the syndrome, our patient had less severe developmental delay. Also, spasticity and loss of mental capacity should not be considered obligatory manifestations of the syndrome because they are not present in half of reported patients, as well as in our family. Origin of the parents of our patient from neighboring villages supports autosomal recessive inheritance of Kohlschütter-T?nz syndrome.     

Gastrointestinal phenotype of ATR-X syndrome

X-linked alpha thalassemia mental retardation (ATR-X) syndrome is associated with profound developmental delay, facial dysmorphism, genital abnormalities, and alpha thalassemia. Patients with ATR-X syndrome frequently present with gastrointestinal problems, in particular feeding difficulties, regurgitation and vomiting, abdominal pain, distension, and chronic constipation. Parental reports of prolonged food refusal and distress in these children are common and although these episodes are suspected to be gastro-intestinal in origin they are rarely investigated. Death in early childhood from aspiration of vomitus or from pneumonia presumed to be secondary to aspiration has been recorded in a number of ATR-X cases. In this report we review the gastrointestinal phenotype of ATR-X syndrome in 128 cases. We also demonstrate that in two siblings, regurgitation was secondary to gastric pseudo-volvulus, a condition in which the stomach does not have a normal system of peritoneal ligaments and changes position with possible torsion around itself. Furthermore, ultra-short Hirschsprung disease with colonic hypoganglionosis was shown and this may contribute to the severe constipation affecting these children.     

Ganglioglioma in a Sotos syndrome patient with an NSD1 deletion

Sotos syndrome, a disorder with macrocephaly, mental delay, and facial anomalies, has been noted to have an increased risk of neoplasia. Here, we report a patient with a microdeletion in nuclear receptor SET-domain-containing protein (NSD1) and a previously undescribed intracranial ganglioglioma.     

A recurrent 1.71 Mb genomic imbalance at 2q13 increases the risk of developmental delay and dysmorphism

Whole genome profiling such as array comparative genomic hybridization has identified novel genomic imbalances. Many of these genomic imbalances have since been shown to associate with developmental delay, intellectual disability and congenital malformation. Here we identified five unrelated individuals who have a recurrent 1.71 Mb deletion/duplication at 2q13 (Human Genome Build 19: 111,392,197-113,102,594). Four of these individuals have developmental issues, four have cranial dysmorphism. Literature review revealed 14 more cases that had similar genomic imbalances at 2q13. Many of them had developmental delay and dysmorphism. Taken together, 93% and 63% of individuals with this genomic imbalance displayed impaired developmental skills and/or abnormal facial features respectively. This copy number variant (CNV) has not been reported in normal control databases. We, therefore, propose that CNV in this region is a risk factor for developmental delay and dysmorphism.     

Kousseff syndrome: a causally heterogeneous disorder

The existence of Kousseff syndrome as a distinct entity has been thrown into doubt by a recent study conducted on the family originally reported by Kousseff. In all cases where chromosome 22q11.2 FISH testing has been undertaken, including the original sibship, a chromosome 22q11.2-microdeletion has been identified. We report two cases of sacral myelomeningocele associated with a conotruncal cardiac anomaly or "Kousseff syndrome." The first case, a 4-year-old girl, had a sacral myelomeningocele, tetralogy of Fallot, microcephaly, hydrocephalus, hypoplasia of the corpus callosum and mild-moderate developmental delay. Chromosome 22q11.2 FISH was normal and the facial phenotype was not that of velocardiofacial syndrome. Sequencing of the entire coding region of CITED2 did not reveal a mutation. The second case, a male infant, was found to have a 22q11.2-microdeletion. These cases confirm Kousseff syndrome to be a causally heterogeneous disorder.     

Chromosomal abnormalities associated with congenital contractures (arthrogryposis)

In a study of 350 patients with multiple congenital contractures (arthrogryposis), 80 (23%) patients had mental retardation or were developmentally delayed. Out of that group of 80 patients, 13 (16%) were found to have abnormal karyotypes. Two of the thirteen had a family history of chromosomal abnormalities without congenital contractures, therefore, 11 patients had chromosomal anomalies which appeared to be associated with the congenital contractures. Five of the eleven (45%) had chromosome mosaicism, three of those had tissue mosaicism. Two had abnormal skin fibroblast cell lines and normal peripheral leukocyte chromosome studies and one had a normal bone marrow karyotype with abnormal peripheral leukocyte chromosome studies. Chromosome studies were done in these patients with congenital contractures because of developmental delay and multisystem involvement, or recognition of clinical features typical of a chromosomal syndrome. We recommend first lymphocyte; and if those are normal, then fibroblast studies be done on all patients with multiple joint contractures and developmental delay, particularly if unusual facial features or multisystem abnormalities are present.     

Infantile hypotonia as a presentation of Rett syndrome

Rett syndrome (RTT) is classically defined by meeting certain clinical diagnostic criteria. It affects mostly females, and one possible pathogenic mechanism was considered to involve mitochondrial function. This was based on the finding of ultrastructural alterations in the mitochondria and decreased respiratory chain enzyme activity. However, the principal etiology of RTT has since been found to be mutations in the MECP2 gene, which is located on the X chromosome. Molecular analysis has allowed the phenotype of MECP2 mutations to be broadened beyond RTT to include girls who have mild mental retardation, autism, and an Angelman syndrome phenotype, as well as males with severe encephalopathy. We present a girl with a previously described mutation in the MECP2 gene whose phenotype is of atypical RTT. She presented with hypotonia and developmental delay in infancy without a clear period of normal development. As part of her evaluation for hypotonia, a muscle biopsy and respiratory chain enzyme analysis showed a slight decrease in respiratory chain enzyme activity consistent with previous reports. This report supports broadening the phenotype of patients who should be considered for MECP2 mutation analysis to include cases of developmental delay and hypotonia without evidence of an initial period of normal development. Furthermore, it supports the hypothesis of an underlying secondary defect in energy metabolism contributing to the pathogenesis of RTT.     

Transmission of ring chromosome 13 from a mother to daughter with both having a 46,XX, r(13)(p13q34) karyotype

Ring chromosomes are thought to be the result of breakage in both arms of a chromosome, with fusion of the points of fracture and loss of the distal fragments. Another mechanism of ring formation is believed to be the simple fusion of chromosome ends with preservation of telomeric and subtelomeric sequences. Ring chromosome 13 was first described in 1968 and its incidence estimated at 1 in 58,000 live births. Severe phenotypes associated with large deletions of 13q have been described as "ring chromosome 13 syndrome." Features of the "ring chromosome 13 syndrome" include mental retardation (often severe), growth retardation, microcephaly, facial dysmorphism, and hand, foot or toe abnormalities. We report on a case of a mother and daughter with r(13) and mild phenotypes. Our patient, IA, had chromosome analysis performed at about 4(1/2) years of age due to some developmental delay. This revealed 46,XX, r(13)(p13q34) karyotype with no loss of any chromosomal band. Her mother, EA, was subsequently found to have the same ring 13. IA's maternal grandmother had a normal karyotype while her maternal grandfather was unavailable for testing. Fluorescence in situ hybridization (FISH) analysis showed loss of a specific subtelomeric 13q region in r(13) in the mother. Clinically, IA had macular hyperpigmentation on the chin and mild delay in speech and fine motor skills. EA, 22 years of age, had mild short stature and borderline mental retardation. To our knowledge, this is the first report of a case of familial transmission of r(13). We compare phenotypes of our cases with those from other reported cases of r(13) and discuss the possible mechanism of formation of this ring chromosome.     

Arnold‐Chiari type 1 malformation in Potocki–Lupski syndrome

Potocki–Lupski syndrome (PTLS) is a genetic disorder that results from an interstitial duplication within chromosome 17p11.2. Children with PTLS typically present with infantile hypotonia, failure to thrive, and global developmental delay with or without major organ system involvement. Systematic clinical studies regarding growth, cardiovascular disease, and neurocognitive profiles have been published; however, systematic evaluation of central nervous system structure by magnetic resonance imaging (MRI) of the brain has not been reported. Herein, we describe three patients with PTLS who were found—in the course of routine clinical care—to have a type 1 Arnold‐Chiari malformation (CM‐1). This finding raises the question of whether the incidence of CM‐1 is increased in PTLS, and hence, if an MRI of the brain should be considered in the evaluation of all patients with this chromosomal duplication syndrome.