Further evidence that the Hajdu-Cheney syndrome and the “serpentine fibula-polycystic kidney syndrome” are a single entity

The Hajdu-Cheney syndrome (HCS) is a rare autosomal dominant disorder. It comprises a coarse face, short neck, hirsutism, joint laxity, and normal intelligence. Bone dysplasias, include acro-osteolysis, bathrocephaly, and vertebral anomalies. In 1988, Exner [1988: Eur J Pediatr 147:544–546] coined the term “serpentine fibula-polycystic kidney syndrome” (SFPKS) when he reported on a girl with short stature, unusual facial appearance, polycystic kidneys, and elongated curved fibulae. He postulated that it was a new entity different from the Melnick-Needles syndrome. Since his report, five similar cases have been published. Similarities between both HCS and SFPKS were noticed first by us and then by other authors. In this report we show that many clinical and radiological characteristics are shared by the HCS and the SFPKS and hypothesize that they represent a single entity with a variable degree of expression. Am. J. Med. Genet. 78:474–481, 1998. © 1998 Wiley-Liss, Inc.     

Clinical and molecular cytogenetic observations in three cases of “trisomy 12p syndrome”

Two unpublished cases with partial tandem duplication of 12p and one previously published case were studied by fluorescence in situ hybridization using 11 cosmid DNA probes from 12p. We propose that the smallest duplications of 12(p13.2pter) and 12(p13.1p13.33) produce the “trisomy 12p syndrome” which is characterized by heavy birth weight, macrocephaly, muscular hypotonia, short neck, flat face, high forehead, prominent cheeks, large philtrum, short nose with anteverted nostrils, and broad everted lower lip. From a review of the published cases we conclude that gross malformations are lacking in “pure” trisomy 12p, and mental retardation is severe in complete and moderate in partial trisomy 12p. Polydactyly and accessory nipples were found only with almost complete trisomy 12p. Abnormalities of hair growth may be related to a gene at 12p. The sub-band 12p11.21 may be critical for acrocallosal syndrome. Macrocephaly may be due to a metabolic disorder. © 1996 Wiley-Liss, Inc.     

Waiting for a diagnosis in Rubinstein–Taybi: The journey from “ignorance is bliss” to the value of “a label”

The journey to receiving a diagnosis for rare genetic disease can be long and emotionally impactful. This study describes parental experiences of receiving their child's diagnosis of Rubinstein–Taybi syndrome (RTS), a rare genetic condition characterized by growth and developmental delay together with dysmorphic features. Parents from the RTS Australia support group participated in qualitative, semi‐structured phone interviews, which were transcribed verbatim and thematically analyzed. Questions focused on psychosocial challenges and benefits pre and post‐diagnosis. Ten mothers and three fathers participated, with the mean age of diagnosis being 8 months. Parents reported positive psychological effects from a slight delay in diagnosis, and negative effects from an extended diagnostic delay, suggesting the ideal time for a parent to receive a diagnosis lies in the post attachment stage, prior to the development of significant parental concerns. This stage would vary depending on condition severity. Parents desired a diagnosis to reduce uncertainty; however, uncertainty remained post diagnosis, and shifted its focus from broadly encompassing etiology and prognosis, to specifically focusing on concerns regarding severity within the spectrum. Perceived benefits of a diagnosis mainly centered on the provision of a label. Parents articulated that a label increased social acceptance, enhanced coping, promoted communication, and improved access to medical, financial, and support services. This study provides insights into the experience of families prior to and following receipt of a diagnosis. It also highlights the possibility of an optimal time window to receive a diagnosis; in which bonding is maximized and parental distress is minimized.     

Sequence analysis and oligonucleotide genotyping of HLA-DR“JX6”, a DR“blank” haplotype found in the Japanese population

We analyzed one of the HLA-DR“blank” haplotypes found in the Japanese population using serologic studies, sequence determination, and genotyping with sequence-specific oligonucleotide (SSO) probes. The DR“blank” haplotype, designated DR“JX6”, segregated in a family in association with the DRw52 and the DQw7 specificities. The cDNA and genomic DNA of the DRB1 gene originating from the DR“JX6” haplotype were amplified enzymatically and sequenced after cloning into a plasmid vector. The amino acid sequence of the first domain in the DRβ1 chain of the DR“JX6” haplotype was different from those of other DR haplotypes sequenced so far, but in the first hypervariable region, the sequence was identical to those of the DRw11, DRw13, DRw14, and DRw17 haplotypes. SSO probes were synthesized on the basis of the DR“JX6” haplotype sequence as well as known sequences of the DRB1, DRB3, and DRB4 genes of other DR haplotypes. These SSO probes were used for the genotyping of Japanese donors whose DRB genes were amplified enzymatically and found to show a hybridization profile that was consistent with the results of serologic studies on the DR“JX6” haplotype.     

Catastrophic antiphospholipid syndrome (CAPS): Descriptive analysis of a series of 280 patients from the “CAPS Registry”

ObjectiveTo describe the clinical and laboratory features, as well as the precipitating factors, treatment and outcome of patients with catastrophic antiphospholipid syndrome (APS).MethodsWe analyzed the 280 patients included until September 2008 in the website based international registry of patients with catastrophic APS (“CAPS Registry”) (http://www.med.ub.es/MIMMUN/FORUM/CAPS.HTM).ResultsThe entire series includes 201 (72%) female and 79 (28%) male patients with a mean age of 37 ± 14 years (range, 11–60 years). A total of 129 (46%) patients suffered from primary APS, 112 (40%) from systemic lupus erythematosus, 14 (5%) from lupus-like disease, and 25 (9%) from other autoimmune diseases. The catastrophic episode was the first manifestation of the APS in 129 (46%) patients. A precipitating factor was reported in 53% of the patients. The first clinical manifestation at the time of the catastrophic episode was a pulmonary complication in 24% of the cases, a neurologic feature in 18% and a renal feature in 18%. During the catastrophic episode, intraabdominal involvement was identified in the majority of patients, mainly consisting of renal (71%), hepatic (33%), gastrointestinal (25%), splenic (19%), adrenal (13%), and pancreatic (8%) manifestations. 123 (44%) patients died at the time of the catastrophic APS event but the higher recovery rate was achieved by the combination of anticoagulants plus corticosteroids plus plasma exchange (PE) and/or intravenous immunoglobulins (IVIG) (69% versus 54%).ConclusionsThe catastrophic APS is an uncommon but potentially life-threatening condition that needs high clinical awareness. The therapeutical connotation is that this may be corrected with the combination of anticoagulation plus steroids plus attempts at achieving a prompt reduction of antiphospholipid antibody titer (i.e. PE and/or IVIG).     

Acromelic frontonasal “dysplasia”: Further delineation of a subtype with brain malformation and polydactyly (Toriello syndrome)

We report on a stillborn boy with frontonasal malformation (Sedano-J?iràsek type D—DeMyer type I), associated with encephalocoele, occipital meningocele and preaxial polydactyly of the feet. This form of frontonasal dysplasia was documented previously in a few other cases with various combinations of postaxial polydactyly, tibial hypoplasia, epibulbar dermoid, occipital encephalocoele, corpus callosum agenesis and Dandy-Walker malformation. Most cases are sporadic.     

Multiple “marker” chromosomes: A novel cytogenetic finding in a patient with mental retardation and congenital anomalies

A patient with mental retardation and clinical manifestations suggestive of Noonan syndrome was found to have in her peripheral lymphocytes multiple small accessory marker chromosomes, varying in number from one to five per cell and in size from about half the size of the q arm of a G group chromosome to less than a centromere. Occasionally, in the more elongated markers, a G-positive or a C-positive band could be identified, or the marker had the appearance of a ring. The origin and significance of these marker chromosomes are discussed.     

Unilateral partial tibia defect with preaxial polydactyly,general micromelia,and trigonomacrocephaly with a note on “developmental resistance”

We report a boy with predominantly unilateral severe tibia defect with a high grade of preaxial polydactyly. Family history suggests the possibility of autosomal dominant inheritance with reduced penetrance and quite variable expressivity. The boy's phenotype and other previously reported examples of predominantly unilateral involvement in autosomal dominant and autosomal recessive limb mutations strongly suggest a hypothesis of developmental resistance in the uninvolved parts.     

“Arias-Stella reaction”-like changes in endocervical glandular epithelium in cervical smears during pregnancy and postpartum states—a potential diagnostic pitfall

A wide spectrum of histologic changes has been described throughout the female genital tract during pregnancy and in the postpartum period. Of these, the endometrial glandular changes referred to as the Arias-Stella reaction have classically been a diagnostic pitfall in histologic sections. Pregnancy-related changes are also reflected in cytologic material obtained from the cervix and vagina. Both glandular and stromal alterations may be seen. The changes involving endocervical glandular epithelium are often alarming enough to cause diagnostic difficulties, especially when the history of pregnancy is not provided. We report 13 cases where marked glandular changes led to diagnostic misinterpretations. These were characterized by cyto- and karyomegaly, a high nuclear to cytoplasmic ratio, round to oval nuclei with smudgy chromatin imparting a ground glass appearance, frequent intranuclear inclusions, and vacuolated to dense variable cytoplasm. The cytologic diagnoses ranged from “glandular atypia” to “suspicious for adenocarcinoma.” Follow-up was available in 11/13 cases. In 9/11 cases, subsequent cervical smears on multiple occasions were negative. Cervical biopsies and/or dilatation and curettage in 4/11 cases did not show significant glandular abnormalities. The glandular changes encountered in cytologic material were similar to those described histologically in the Arias-Stella reaction involving the cervix. This similarity and the fact that these changes disappeared upon termination of the pregnancy favors the presumption that they represent the Arias-Stella reaction. Awareness of these changes during pregnancy and postpartum may prevent interpretive errors and unnecessary surgical procedures. Diagn Cytopathol 1996;14:349–355. © 1996 Wiley-Liss, Inc.     

A phenotypically severe,biochemically “silent” case of HIBCH deficiency in a newborn diagnosed by rapid whole exome sequencing and enzymatic testing

3‐Hydroxyisobutyryl‐CoA dehydrogenase (HIBCH) deficiency is a rare error in valine catabolism associated with a Leigh syndrome‐like phenotype, mitochondrial dysfunction, and increased C4‐OH. We report the most severe case to date in a full‐term female who presented with poor feeding and nystagmus on day of life (DOL) 1. Although initial neuroimaging findings were concerning for metabolic disease, further metabolic testing was nondiagnostic and she was discharged on DOL 18. She was readmitted on DOL 22 after severe apneic episodes requiring intubation, with EEG demonstrating multifocal seizures and MRI/MRS demonstrating worsening findings. Care was withdrawn DOL 27 and she expired. Rapid whole exome sequencing (WES) demonstrated compound heterozygous variants in HIBCH with a paternal pathogenic variant (c.852delA, p.L284FfsX10 ) and a maternal likely pathogenic variant (c.488G>T, p.C163F). Fibroblast enzymatic testing demonstrated marked reduction in HIBCH levels. This case demonstrates the importance of rapid WES and follow‐up functional testing in establishing a diagnosis when metabolic disease is suspected but lacks an expected biochemical signature.     

“I'm not a patient,I'm a person”: The Experiences of Individuals With Intellectual Disabilities and Challenging Behavior—A Thematic Synthesis of Qualitative Studies

Individuals with intellectual disabilities (ID) and challenging behavior often have complex care needs and may be reliant on care support services. This thematic synthesis examines published qualitative research on the experiences of individuals with ID in relation to received service supports and interventions. Seventeen studies met criteria. Four themes emerged: (1) Imbalance of power, (2) Causal attributions about challenging behavior, (3) Experiences of restrictive interventions, and (4) Opportunities for improvement: proactive interventions. The accumulative stressors of living in a residential placement were regarded as a cause of continued challenging behaviors. The impersonal attitude of support staff was regarded as a major contributory factor. The findings can inform service providers about how best to support individuals with ID and challenging behavior.