Duplication of the Wolf-Hirschhorn syndrome critical region causes neurodevelopmental delay

Wolf-Hirschhorn Syndrome (WHS) is caused by deletions on chromosome 4p and is clinically well defined. Genotype-phenotype correlations of patients with WHS point to a critical locus to be responsible for the main characteristics of this disorder. Submicroscopic duplications of this region, however, are not known. Here we report a patient with an interstitial 560 kb duplication overlapping this critical locus. The present case shows that not only deletions but also duplications of the Wolf-Hirshhorn critical region cause mental retardation and multiple congenital anomalies. Interestingly, the duplication phenotype overlaps partially with the deletion phenotype. However, his facial phenotype differs from the typical WHS gestalt.     

Delimiting the Wolf-Hirschhorn syndrome critical region to 750 kilobase pairs

Wolf-Hirschhorn syndrome (WHS) is a multiple anomaly condition characterized by mental and developmental defects, resulting from the absence of the distal segment of one chromosome 4 short arm (4p16.3). Owing to the complex and variable expression of this disorder, it is thought that the WHS is a contiguous gene syndrome with an undefined number of genes contributing to the phenotype. The 2.2 Mbp genomic segment previously defined as the critical region by the analyses of patients with terminal or interstitial deletions is extremely gene dense and an intensive investigation of the developmental role of all the genes contained within it would be daunting and expensive. Further refinement in the definition of the critical region would be valuable but depends on available patient material and accurate clinical evaluation. In this study, we have utilized fluorescence in situ hybridization to further characterize a WHS patient previously demonstrated to have an interstitial deletion and demonstrate that the distal breakpoint occurs between the loci FGFR3 and D4S168. This reduces the critical region for this syndrome to less than 750 kbp. This has the effect of eliminating several genes previously proposed as contributing to this syndrome and allows further research to focus on a more restricted region of the genome and a limited set of genes for their role in the WHS syndrome. Am. J. Med. Genet. 71:47–53, 1997. © 1997 Wiley-Liss, Inc.     

The Wolf-Hirschhorn (4p-) syndrome

In a review of 43 cases, the phenotypic spectrum of the Wolf-Hirschhorn syndrome is analyzed and the frequency of clinical anomalies is tabulated. The characteristic features are intrauterine growth retardation, severe psychomotor retardation, typical facies, and various major and minor congenital anomalies suggestive of a midline fusion defect. Diagnosis is established by karyotyping - deletion of the short arm of chromosome No. 4. All cases so far reported are de novo occurrences with no sibling involvement and normal parents. Prognosis is poor, with death in the first 2 years of life in 34 % of cases, usually due to cardiac decompensation or infection. Psychomotor retardation is profound, so that heroic medical efforts probably need to be reconsidered.     

First known microdeletion within the Wolf-Hirschhorn syndrome critical region refines genotype-phenotype correlation

Deletions within HSA band 4p16.3 cause Wolf-Hirschhorn syndrome (WHS), which comprises mental retardation and developmental defects. A WHS critical region (WHSCR) of approximately 165 kb has been defined on the basis of 2 atypical interstitial deletions; however, genotype-phenotype correlation remains controversial, due to the large size of deletion usually involving several megabases. We report on the first known patient with a small de novo interstitial deletion restricted to the WHSCR who presented with a partial WHS phenotype consisting only of low body weight for height, speech delay, and minor facial anomalies; shortness of stature, microcephaly, seizures and mental retardation were absent. The deletion was initially demonstrated by FISH analysis, and breakpoints were narrowed with a "mini-FISH" technique using 3-5 kb amplicons. A breakpoint-spanning PCR assay defined the distal breakpoint as disrupting the WHSC1 gene within intron 5, exactly after an AluJb repeat. The proximal breakpoint was not found to be associated with a repeated sequence or a known gene. The deletion encompasses 191.5 kb and includes WHSC2, but not LETM1. Thus, manifestations attributable to this deletion are reduced weight for height, minor facial anomalies, ADHD and some learning and fine motor deficiencies, while seizures may be associated with deletions of LETM1.     

A microdeletion proximal of the critical deletion region is associated with mild Wolf-Hirschhorn syndrome

It is generally accepted that the facial phenotype of Wolf-Hirschhorn syndrome is caused by deletions of either Wolf-Hirschhorn critical regions 1 or 2 (WHSCR 1-2). Here, we identify a 432?kb deletion located 600?kb proximal to both WHSCR1-2 in a patient with a WHS facial phenotype. Seven genes are underlying this deletion region including FAM193a, ADD1, NOP14, GRK4, MFSD10, SH3BP2, TNIP2. The clinical diagnosis of WHS facial phenotype was confirmed by 3D facial analysis using dense surface modeling. Our results suggest that the WHSCR1-2 flanking sequence contributes directly or indirectly to the severity of WHS. Sequencing the Wolf-Hirschhorn syndrome candidate 1 and 2 genes did not reveal any mutations. Long range position effects of the deletion that could influence gene expression within the WHSCR were excluded in EBV cell lines derived from patient lymphoblasts. We hypothesize that either (1) this locus harbors regulatory sequences which affect gene expression in the WHSCR1-2 in a defined temporal and spatial developmental window or (2) that this locus is additive to deletions of WHSCR1-2 increasing the phenotypic expression.     

Laurin-Sandrow syndrome (mirror hands and feet and nasal defects): description of a new case.

A child with complete syndactyly of cup shaped hands and mirror polysyndactyly of the feet, together with a nasal defect, was identified out of a total of 1,031,439 livebirths. She had a pattern of multiple congenital anomalies which was similar to that first described by Laurin et al in 1964 and by Sandrow et al in 1970. Two more cases with a similar pattern of congenital anomalies have recently been published so this is the fifth reported case with this constellation.     

Oculo-palatal-cerebral syndrome: a second case

Oculo-palato-cerebral syndrome is an extremely rare disorder consisting of low birth weight, microcephaly, short stature, persistent hyperplastic primary vitreous, microphthalmia, large ears, small hands and feet, cleft palate, joint hypermobility, developmental delay, and cerebral atrophy. There has been one report of a consanguineous family with three affected children, suggesting autosomal recessive inheritance. We report on the second case of this disorder. Our patient, a 2-year-old boy, had growth delay, microcephaly, bilateral persistent hyperplastic primary vitreous with right microphthalmia, long ears with thickened helices, small hands and feet, highly arched palate, joint hypermobility, hypoplastic nails, frontal cerebral atrophy and thinning of the corpus callosum on brain magnetic resonance imaging, and mild developmental delay. He has much milder features than those seen in the previously reported cases.     

Oculocerebral syndrome with hypopigmentation (Cross syndrome): report of a new case

A syndrome of ocular and cutaneous hypopigmentation, severe mental retardation with spastic tetraplegia and athetosis was first observed by Cross in three siblings of an inbred Amish family. Since then, seven other patients, three sporadic and four with familial recurrence, have been reported in the literature, confirming the autosomal recessive inheritance. The clinical spectrum of the syndrome has been expanded to include true developmental defects of the CNS such as cystic malformation of the posterior fossa of the Dandy-Walker type. We report a new case of Cross syndrome.     

Pathologic findings in the Wolf-Hirschhorn (4p-) syndrome

We describe a 1-month-old female with the Wolf-Hirschhorn syndrome. GTG-banding studies disclosed a 46,XX,del(4)(:p15 → qter) in the child and apparently normal chromosomes in the parents. Autopsy at 4 months showed hypoplasia of most organs.     

A new case of mosaicism for invdup(15) duplicated for Prader-Willi/Angelman syndrome critical region (PWACR) in an adult healthy man

Supernumerary invdup(15) chromosomes, now also reported as sSMC(15), containing two additional copies of Prader–Willi/Angelman critical region (PWACR) have been associated with distinct clinical phenotype that includes hypotonia, dysmorphisms, developmental delay/mental retardation, autistic behaviour, and epilepsy.

We report on a healthy adult male carrying an sSMC(15) with two copies of PWACR in 20–50% of cells from different tissues. Molecular analyses showed the sSMC(15) as resulting from a PWACR-duplicated region spanning 8 Mb which is larger than those in the only two other healthy PWACR-duplicated sSMC(15) carriers previously reported.

Mosaicism level and mosaic cell line rate variation among different tissues observed in our case support mosaicism in critical tissues as of relevance for sSMC(15) phenotype–genotype correlations.     

Postaxial acrofacial dysostosis (Miller) syndrome: a new case.

We describe a new case of postaxial acrofacial dysostosis (Miller) syndrome. This syndrome consists of mandibulofacial dysostosis, similar to that seen in Treacher Collins syndrome, and postaxial limb deficiency. The mode of inheritance remains uncertain.     

Hemifacial myohyperplasia: description of a new syndrome.

Hemifacial hypertrophy is a rare condition characterized by unilateral enlargement of all tissues of the face. We describe three patients who exhibit hemifacial hyperplasia of the muscles of facial expression with no other organ system involvement. These three cases, in addition to six other cases identified in the literature, describe a unique constellation of characteristics that place these patients into a distinct syndrome. We suggest that the term "hemifacial myohyperplasia" be used to describe this specific and unique condition.     

Hepatitis-associated aplastic anemia: description of a new case

Hepatitis-associated aplastic anemia is an only recently recognised syndrome. We present a case whereby a month after an episode of fever, a 17-year-old boy was recovered with liver enzyme elevation and circulating platelet reduction. All the acute viral hepatitis markers were negative. After bone marrow aspiration a severe aplastic anemia was diagnosed and all the findings were consistent with hepatitis-associated aplastic anemia. The disorder was initially treated with glucocorticoids and platelet transfusion, obtaining the normalization of the liver enzymes but worsening of the aplastic anemia. An HLA-identical related marrow donor was not found. The patient responded to immunosuppressive treatment but died of multi-organ failure due to severe sepsis.     

The elusive Angelman syndrome critical region.

DNA mapping studies in two families provide further information on the Angelman syndrome critical region, which has recently been defined by the gene UBE3A. The first family has probable familial Angelman syndrome with a maternally imprinted inheritance pattern. A 5 year old girl with this disorder has a 14 year old brother and an 11 year old male cousin who have less typical clinical features. DNA microsatellite analysis has shown that the three share a common segment of the same grandpaternal chromosome 15q11-q13 that overlaps with UBE3A. The child with typical Angelman syndrome has an additional maternal recombination 5' to UBE3A. The second family is a mother and son both of whom have mental retardation but no other features of Angelman syndrome despite an extensive DNA deletion on the telomeric side of UBE3A. Together, the two families identify a region between loci D15S210 and D15S986 which forms part of the Angelman syndrome critical region. A new microsatellite (D15S1234) is described which can be used in place of the LS6-1 marker at locus D15S113.     

The NEU-COFS (cerebro-oculo-facio-skeletal) syndrome: report of a case

A newborn female with a phenotype intermediate between the Neu and the COFS syndromes is described.
The hypothesis of the two conditions representing different degrees of severity of the same autosomal recessive mutation in the homozygote state is discussed.