Mutations in CKAP2L,the Human Homolog of the Mouse Radmis Gene,Cause Filippi Syndrome

Filippi syndrome is a rare, presumably autosomal-recessive disorder characterized by microcephaly, pre- and postnatal growth failure, syndactyly, and distinctive facial features, including a broad nasal bridge and underdeveloped alae nasi. Some affected individuals have intellectual disability, seizures, undescended testicles in males, and teeth and hair abnormalities. We performed homozygosity mapping and whole-exome sequencing in a Sardinian family with two affected children and identified a homozygous frameshift mutation, c.571dupA (p.Ile191Asnfs^∗6), in CKAP2L, encoding the protein cytoskeleton-associated protein 2-like (CKAP2L). The function of this protein was unknown until it was rediscovered in mice as Radmis (radial fiber and mitotic spindle) and shown to play a pivotal role in cell division of neural progenitors. Sanger sequencing of CKAP2L in a further eight unrelated individuals with clinical features consistent with Filippi syndrome revealed biallelic mutations in four subjects. In contrast to wild-type lymphoblastoid cell lines (LCLs), dividing LCLs established from the individuals homozygous for the c.571dupA mutation did not show CKAP2L at the spindle poles. Furthermore, in cells from the affected individuals, we observed an increase in the number of disorganized spindle microtubules owing to multipolar configurations and defects in chromosome segregation. The observed cellular phenotypes are in keeping with data from in vitro and in vivo knockdown studies performed in human cells and mice, respectively. Our findings show that loss-of-function mutations in CKAP2L are a major cause of Filippi syndrome.     

Two brothers with atypical syndactylies,cerebellar atrophy and severe mental retardation

Two brothers with a combination of atypical syndactylies, cerebellar atrophy and severe mental retardation are described. These cases share important features with the group of craniodigital syndromes and could represent new occurrences of Filippi syndrome. Cerebellar atrophy may represent a yet unreported finding in this syndrome.     

Neuroleptic malignant syndrome: occurrence in a child after reconstructive surgery

The occurrence of the rare but potentially fatal neuroleptic malignant syndrome must be considered by the surgeon treating a patient who develops hyperthermia, mental abnormalities, autonomic instability, and muscle rigidity after exposure to phenothiazines or other neuroleptic drugs. The dopamine agonist bromocriptine appears to be the treatment of choice in adults and seemed to be effective and well tolerated in our patient. Although the syndrome cannot be prevented, recognition is crucial, since effective general and specific therapy is available. Differentiating neuroleptic malignant syndrome from malignant hyperthermia allows early appropriate treatment with bromocriptine.     

The surgical treatment of congenital webbing (pterygium) of the popliteal area.

We describe a case of congenital popliteal pterygium in conjunction with other specific congenital malformations. This syndrome has been called the quadruple syndrome. The literature is reviewed. A rationale for more aggressive treatment of this deformity is discussed. One child who has undergone major multiple nerve grafts as a part of the primary corrective surgery is reported. Her result has been pleasing to the patient, the parents, and the surgeons.     

Macrocephaly-cutis marmorata telangiectatica congenita: report of a patient with a translocation

Cutis marmorata telangiectatica congenita (CMTC) is a rare cutaneous disorder. More than one half of the patients with CMTC have additional extra-cutaneous associated congenital anomalies. A subset of patients with CMTC have macrocephaly, the M-CMTC syndrome. This is a report on a patient with the M-CMTC syndrome and a de novo translocation t(2;17)(p11;p13). The etiology and pathology of the M-CMTC syndrome is unknown. Suggestions for the cause for M-CMTC include the occurrence of a new dominant mutation in a single gene, deletion of multiple contiguous genes at a level beyond the resolution of conventional karyotyping and chromosomal mosaicism. This patient did not have chromosomal mosaicism, however he had a translocation. It can be postulated that in the present patient the translocation breakpoints disrupted one or more genes entailing skin lesions but also other features: mental retardation, macrocephaly and facial dysmorphia.     

Deletion within the CYP17 gene together with insertion of foreign DNA is the cause of combined complete 17 alpha-hydroxylase/17,20-lyase deficiency in an Italian patient.

The molecular basis of 17 alpha-hydroxylase/17,20-lyase deficiency syndrome in a 14-yr-old 46,XY Italian patient was investigated by amplification, subcloning, and sequencing of specific exonic sequences from genomic DNA samples. A homozygous mutation, consisting of a 518-basepair (bp) deletion combined with a 469-bp insertion, was identified in the CYP17 gene of the patient. The deletion spans much of exon II, the whole intron 2, and a portion of exon III. A part (156 bp) of the inserted sequence shows 95.5% identity to the nuclear antigen-binding site on Marek disease virus DNA and sequences found in rearranged mitochondrial DNA of rat hepatoma cells. A similar degree of sequence identity (99%) was also found between the above sequences and part of the lac operon of E. coli. The inserted sequence is lacking the BamHI site in intron 2 of CYP17 and contains an in-frame stop codon (TAA). Thus, the mutated gene encodes a truncated nonfunctional steroid hydroxylase, giving rise to symptoms associated with complete combined 17 alpha-hydroxylase/17,20-lyase deficiency. The family history revealed that the patient is the child of a consanguineous marriage and has two genotypically and phenotypically female sisters also suffering from symptoms of the disease. Investigation of genomic DNA from these sisters revealed that in each case both CYP17 alleles contained the same mutation. On the other hand, the parents were found to be heterozygous for this mutation. The insertion could not be found in DNA from normal individuals or in the CYP17 gene of other Italian patients with the 17 alpha-hydroxylase deficiency syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)     

Agenesis of corpus callosum,ocular, and skeletal anomalies (X-linked dominant aicardi's syndrome) in a girl with balanced X/3 translocation

Summary Aicardi's syndrome, which is characterized by agenesis of the corpus callosum, specific chorioretinal abnormalities, and defects of vertebrae and ribs, is considered a probable X-linked dominant trait with male lethality. All features of this syndrome were seen in a girl with a de novo balanced X/3 translocation (46,X,t(X;3)(p22;q12)). It is hypothesized that the clinical picture is the consequence of chromosome breakage within the Aicardi locus. Then, unusual X-inactivation patterns in blood and fibroblasts of this patient can be explained by somatic selection against cells with the Aicardi phenotype.     

Glaucoma in a patient with subclavian steal syndrome

Vascular disease may be an underlying factor in certain patients with normal tension glaucoma. Normal tension glaucoma patients with specific vascular and neurological symptoms, in correlation with results of clinical tests (i.e. intraocular pressure, ophthalmodynamometry, blood pressure), will benefit from a further work-up for systemic vascular disease. Subclavian steal syndrome is one such vascular disease which can produce symptoms and clinical signs which alert the clinician to evaluate the patient further. Subclavian steal syndrome can potentially decrease perfusion to the optic nerve head, making it more susceptible to glaucomatous cupping in the presence of normal intraocular pressures. The following case report illustrates a patient who developed subclavian steal syndrome and contralateral optic nerve head hypoperfusion.     

High incidence of free monoclonal lambda light chains in the sera of patients with Sjogren's syndrome

Sjogren's syndrome presents a wide spectrum of disease manifestations ranging from benign to malignant lymphoproliferation. Sera from 21 patients with primary Sjogren's syndrome, 63 patients with other autoimmune rheumatic diseases, and 140 normal controls were studied by using high-resolution gel electrophoresis combined with immunofixation and specific absorption studies. Two-thirds of the sera from Sjogren's syndrome patients contained free monoclonal lambda light chains. In addition, one patient with Sjogren's syndrome and pseudolymphoma had a circulating monoclonal IgM-lambda immunoglobulin. In contrast, only 16% of the patients with other autoimmune diseases and 5% of normals had monoclonal bands; none of the other patients studied exhibited monoclonal-free lambda light chains in their serum. Our findings suggest that the monoclonal process in Sjogren's syndrome starts early in the disease process in a subset of B cells.     

Opitz-C syndrome: on the nosology of mental retardation and trigonocephaly.

We report on two patients with a complicated form of trigonocephaly. The first patient has the Opitz-"C"-trigonocephaly syndrome. The second patient had initially a delayed motor development, but finally attained normal intelligence. A review of 22 patients with Opitz-C syndrome from the literature is presented. Most of the typical facial dysmorphism can be regarded as part of a trigonocephaly "sequence" rather than presenting characteristic features of a syndrome. More specific are the intra-oral anomalies, abnormally modelled ears, cardiac anomalies and neonatal hypotonia. All surviving patients are severely retarded. Since almost all patients are sporadic cases we suggest that the "C"-syndrome is a cytogenetically yet undetectable microdeletion syndrome.     

Report of a patient with T-cell deficiency and normal B-cell function: A new immunodeficiency disease with response to transfer factor

An 11-yr-old boy had recurrent fevers and pulmonary infections since early childhood and, at age 7, had disseminated varicella with bilateral pneumonitis. A female sibling, age 1, died during this period of time with varicella pneumonia. Two years later, an immunological evaluation showed severe deficits in cellular immunity with skin anergy and very low or poor in vitro lymphocyte proliferative responses to mitogens, allogeneic cells and specific antigens. Quantitation of peripheral T-cells by spontaneous rosette formation was also low—40–45% (normal 61%). On the other hand, B-cell immunity seemed to be completely normal. Serum immunoglobulins and the immunoglobulin receptors on peripheral lymphocytes were normal. The patient produced specific antibodies upon antigen challenge (immunization) and after natural infection. Following transfer factor therapy, conversion of skin reactivity and clinical improvement occurred. No changes were seen in in vitro lymphocyte function with transfer factor therapy. Immunologic reconstitution persisted for 6 mo, after which the patient responded again to the administration of transfer factor. Although this patient has several characteristics in common with Nezelof's syndrome, the patient described in this report appears to represent a distinct clinical entity of primary isolated T-cell deficiency and normal B-cell immunity. The normal B-cell immune system, and the clinical and immunological response to transfer factor therapy, differentiates our patient from the syndrome of thymic dysplasia with immunoglobulin synthesis (Nezelof's syndrome).     

Severe congenital limb deficiencies,vertebral hypersegmentation,absent thymus and mirror polydactyly: A defect expression of a developmental control gene?

We describe two unrelated patients with a complex malformation pattern that may be a candidate for a developmental gene disorder. These two patients had severe, symmetrical upper and lower limb deficiencies, vertebral hypersegmentation, and duodenal atresia. Patient 1 also had mirror-image polydactyly of his feet; patient 2 was athymic. The concurrence in two unrelated patients of additional vertebrae with severe anomalies in limb development, including a symmetrical deficiency of the four limbs and either mirror-image duplication of some toes (only in patient 1) or absence of the thymus (only in patient 2), represents an early alteration in body-plan organization. Since limb development, thymus development and segmentation are possibly under the control of homeobox genes in the human embryo, it seems reasonable that the malformations observed in these two patients resulted from a defect of a gene controlling developmental pattern formation, possibly a homeobox gene or a paired-box gene. Severe limb deficiencies have been reported in other well-known genetic entities, such as Roberts syndrome, Baller-Gerold syndrome, X-linked amelia, and DK-phocomelia syndrome. However, since the specific pattern of anomalies observed in these patients makes the diagnosis of some of the abovementioned disorders unlikely, we conclude that our patients have a previously undescribed disorder.     

8q12.1q12.3 de novo microdeletion involving the CHD7 gene in a patient without the major features of CHARGE syndrome: Case report and critical review of the literature

CHARGE syndrome is an autosomal dominant inherited disorder characterized by a specific and recognizable pattern of anomalies. De novo mutations or deletions of the gene encoding chromodomain helicase DNA binding protein 7 (CHD7) are the major cause of CHARGE syndrome. In this report, we describe a patient with a typical phenotype characterized by psychomotor retardation, hypertrichosis, facial asymmetry, synophria, failure to thrive, developmental delay and gastro-esophageal reflux, carrying a de novo 6.04 Mb interstitial deletion in 8q12.1q12.3 detected by single nucleotide polymorphism (SNP) array analysis. Despite the deletion includes CHD7 and although the patient shares some of the clinical features of the CHARGE syndrome, she does not fulfill the clinical criteria for this syndrome. To the best of our knowledge, this is the second case with an entire deletion of the CHD7 gene not leading to CHARGE syndrome and, for this reason, useful to expand and further delineate the clinical features associated with the 8q12.1q12.3 deletion. Furthermore, the literature review revealed that the phenotype secondary to duplications of the same region partially overlaps with the phenotype reported in this study. Selected genes that are present in the hemizygous state and which might be important for the phenotype of this patient, are discussed in context of the clinical features.     

Glycoproteomic studies of IgE from a novel hyper IgE syndrome linked to PGM3 mutation

Glycans serve as important regulators of antibody activities and half-lives. IgE is the most heavily glycosylated antibody, but in comparison to other antibodies little is known about its glycan structure function relationships. We therefore describe the site specific IgE glycosylation from a patient with a novel hyper IgE syndrome linked to mutations in PGM3, which is an enzyme involved in synthesizing UDP-GlcNAc, a sugar donor widely required for glycosylation. A two-step method was developed to prepare two IgE samples from less than 1 mL of serum collected from a patient with PGM3 mutation and a patient with atopic dermatitis as a control subject. Then, a glycoproteomic strategy was used to study the site-specific glycosylation. No glycosylation was found at Asn264, whilst high mannose glycans were only detected at Asn275, tri-antennary glycans were exclusively observed at Asn99 and Asn252, and non-fucosylated complex glycans were detected at Asn99. The results showed similar glycosylation profiles between the two IgE samples. These observations, together with previous knowledge of IgE glycosylation, imply that IgE glycosylation is similarly regulated among healthy control, allergy and PGM3 related hyper IgE syndrome.     

Chromosome 22q11.2 microdeletion in a patient with hemophilia A

We report a 6-year-old patient with hemophilia A, who also exhibited clinical features typical of 22q11.2 deletion syndrome (22qDS). The specific traits were mild mental retardation, speech delay, hypernasal speech, deficits in voice quality and articulation, narrow palpebral fissures, broad and depressed nasal root, high-arched palate, microstomia, and overfolded ears. The patient had no associated congenital cardiac or palatal malformations. It can be particularly difficult to identify this syndrome in newborns and infants without congenital heart defects. This case underlines that microdeletion of chromosome 22q11.2 should be considered in any patient who exhibits typical clinical features of 22qDS, regardless of whether they have another single-gene disorder.     

Urinary excretion of LATS in a patient with Graves' disease complicated by nephrotic syndrome

A case report of a female patient with Graves' disease complicated by nephrotic syndrome with high LATS activity in urinary gamma-globulin is presented. When in the hyperthyroid state with high LATS activity in the serum, she was treated with antithyroid drugs, excess iodine, and finally radioisotopes. Mild hypothyroidism occurred transiently without any significant change in serum LATS activity. Nephrotic syndrome suddenly appeared. Urinary IgG was purified by salting out with ammonium sulfate, DEAE and protein A-Sepharose, and LATS activity in the purified urinary IgG fraction was demonstrated. The specific activity of LATS activity in urinary IgG protein was slightly lower than that of the serum. This case is the first demonstration of LATS activity in urine from a patient with hyperthyroidism and nephrotic syndrome.     

Interstitial telomeric sequences at the junction site of a jumping translocation

The mechanism(s) for the origin of jumping translocations (JTs) are unknown. To assess the possible involvement of telomeric sequences in the jumping process, metaphases of a patient with hydrops fetalis having a JT were analyzed for the presence of interstitial telomeres. Telomere DNA sequences were detected at the junction sites of the donor and the recipient chromosomes. Interstitial telomeric sequences have so far only been detected in JTs involving chromosome 15q in patients with Prader-Willi syndrome. Our finding of interstitial telomeric sequences in a JT with a chromosome different from chromosome arm 15q in a patient without Prader-Willi syndrome implies that telomere sequences may be common to all telomeric JTs. The possible role of telomeric sequences as a cause of the observed chromosomal mosaicism is discussed. Received: 24 September 1996 / Revised: 15 December 1996     

11q- syndrome: three cases and a review of the literature.

We report on three children with de novo terminal deletions of the long arm of chromosome 11 (11q-) and breakpoints in 11q23-q24. Eighty-nine other patients with partial monosomy 11q have been reported and were reviewed by us. Salient features of 11q- syndrome are psychomotor retardation, trigonocephaly, telecanthus/hypertelorism, broad depressed nasal bridge, micrognathia, low set abnormal ears, cardiac anomalies and hand/foot anomalies. Renal agenesis and anal atresia are reported first here. Supratentorial white matter abnormality on CT and MRI present in our second patient was reported in three patients. Increased mortality is caused by cardiac anomalies. A third of all patients with partial monosomy 11q had thrombocytopenia or pancytopenia and this seems to be related to the absence of band 11q23-q24. Seventy-six percent of patients have de novo deletions with breakpoints in 11q21-q25. There is no obvious correlation between the length of the deleted segment and the severity of the symptoms. In unbalanced chromosomal patterns with deletions of 11q involving bands 11q23-q24 the typical phenotype of 11q- syndrome remains recognizable. Deletions distal to 11q24.1 do not produce the typical 11q- syndrome.     

Structural chromosome abnormalities in Down syndrome: a study of two families.

Two families were ascertained through a proband with Down syndrome and a structural rearrangement involving two chromosomes 21. It is suggested that in one patient the chromosome is an isochromosome formed by misdivision of the centromere of a maternal telocentric chromosome 21 and that in the other a Robertsonian translocation involving chromosome 21 was inherited from the mother, who is a 46,XX/46,XX, -21,+t(21q21q) mosaic. The origin of the mosaicism is discussed and considered to be likely to be the result of breakage and reunion at the chromatid, rather than the chromosome, level.     

Isolation and characterization of human thyrotropin-releasing hormone (TRH) from an endocrine pancreatic tumor

An extract of a pancreatic carcinoid tumor obtained at autopsy from a patient who had suffered from Cushing's syndrome was found to have the ability to release thyrotropin (but not any other pituitary hormones) from cultured rat anterior pituitary cells, and to bind to a specific thyrotropin-releasing hormone (TRH) antiserum. The tumor contained 2.2 and 3.9 nmol/g of TRH bio- and immunoreactivity, respectively. The active material was purified and its amino acid composition and chromatographic properties were found to be identical with those of synthetic ovine/porcine TRH. This represents the first isolation of human TRH and the first established case of a 'TRHoma', a TRH-producing tumor.