A novel mutation in the FOXC1 gene in a family with Axenfeld-Rieger syndrome and Peters' anomaly

Peters anomaly and Axenfeld-Rieger syndrome (ARS) belong to the overlapping spectrum of disorders summarized as anterior segment dysgenesis (ASD). Five patients from a family with Peters' anomaly and ARS were screened for mutations in the PITX2, CYP1B1 and FOXC1 genes by direct sequencing. All affected family members examined were heterozygous for a single nucleotide substitution, resulting in a nonsense mutation (Q120X) at a highly conserved residue of the FOXC1 gene that is essential for DNA binding. In this pedigree, all affected family members were diagnosed with ARS except for one who shows bilateral Peters' anomaly. Our findings support the role of FOXC1 mutations in the spectrum of ASD.     

Brachydactylic multiple delta phalanges plus syndrome

Delta phalanges are unusual, shortened bones of the hands and feet with abnormal epiphyses and diaphyses. Here, we report on a patient with a unique multiple congenital anomaly syndrome that includes brachydactyly consisting of multiple delta phalanges in several digits of the hands and feet. The patient, who was born to consanguineous parents, had several other congenital anomalies, including butterfly vertebrae, craniofacial dysmorphism, and coarctation of the aorta. We have called this distinctive condition "brachydactylic multiple delta phalanges plus syndrome." Although no other member of the family had obvious hand or foot anomalies, several siblings had other malformations. Possible modes of inheritance in this family include variable expression of a recessive or de novo dominant condition.     

A case of Peters' anomaly in a springer spaniel.

An 8-week-old springer spaniel presented with a large central corneal opacity of the left globe, which was accompanied by cords of tissue spanning from the iris collarette to the posterior cornea. A posterior cortical cataract was noted in the right eye. At the owner's request the puppy was humanely destroyed, and a necropsy was performed. Upon sectioning the left globe in the vertical plane, a circle of pigmented strands of tissue was observed spanning the anterior chamber from the iris to the posterior aspect of the cornea. The right globe appeared normal when inspected grossly. Histologically, a membrane of pigmented tissue covered the posterior aspect of the broad central corneal leukoma of the left globe. This membrane and the cords traversing the anterior chamber were composed of vascular uveal tissue. Descemet's membrane and the corneal endothelium were reduced or absent in the zone of corneal opacity. Other than the changes associated with cataract, the right globe was histologically normal. The clinical and histological findings in the left globe were identical with those described for Peters> anomaly in human beings.     

An Indian child with Coats plus syndrome due to mutations in STN1

The role of the CTC1–STN1–TEN1 (CST) complex in Coats plus syndrome (CP), as well as other telomeropathy‐phenotypes and disorders of genome instability is well documented. We report an Indian child with a clinical diagnosis of CP who presented to us with retinal exudates, extensive cerebral calcification, developmental delay and severe anemia consequent upon chronic gastrointestinal (GI) bleeding. Whole exome sequencing revealed compound heterozygous variants in STN1 as the probable genetic cause leading to CP in the present case. Of the two variants, the nonsense variant c.397C>T (p.Arg133*) was a truncating variant leading to loss of full protein length whereas the second variant c.985G>C (p.Ala329Pro) was novel and neither reported in ExAC, 1KGP or gnomAD. The deleteriousness of the novel variant was explored through molecular dynamics simulation analysis where p.Ala329Pro mutation affected C‐terminal domain interaction between STN1 and TEN1 complex. Hormonal therapy using ethinyl estradiol and norethisterone was apparently associated with a clinically useful, although poorly sustained, decrease in blood transfusion requirement in the proband.     

Blepharophimosis plus ovarian failure: a likely candidate for a contiguous gene syndrome.

We describe four females from three families with blepharophimosis, epicanthus inversus, and ptosis who were found to have premature ovarian failure. In two families the inheritance was autosomal dominant and in one it was a new mutation. Two females had, in addition, dysmorphic facial features which have been described in other cases. We suggest that the aetiology of the blepharophimosis ovarian failure syndrome is a contiguous gene syndrome.     

Detection and partial characterization of immune complexes in patients with rheumatoid arthritis plus Sjogren's syndrome and with Sjogren's syndrome alone.

In order to characterize the immune complexes detected in patients with Sjogren''s syndrome (SS) and with rheumatoid arthritis (RA), the sera of 19 patients with SS alone and 11 with SS plus RA were examined. Elevated quantities of circulating immune complexes (CIC) were detected in 67% by the C1q-binding assay (C1q-BA), 73% by the C1q-solid phase (C1q-SP) assay, 43% by the monoclonal rheumatoid factor solid phase assay (mRF-SP) and 33% by the mRF-inhibition assay (MRF-Inh). Elevated concentrations of IgM RF were detected in 83% and of IgG RF in 73% of the sera by radioimmunoassay. Strong correlations existed between RF of the IgM and IgG classes and both the C1q-BA and the C1q-SP. Three lines of evidence indicated that RF were important components of the immune complexes detected by these radioimmunoassays. These results indicated that in those patients with RA plus SS, as well as those with SS alone, both IgM and IgG RF made substantial contributions to immune complexes detected both by C1q-BA and C1q-SP.     

Growth hormone deficiency (GHD): a new association in Peters' Plus Syndrome (PPS)

We report a case of a girl with clinical features of Peters' Plus Syndrome (PPS) (association of anterior eye chamber defects; peculiar facies; cleft lip/palate; brachymelia; developmental delay; growth retardation) and documented growth hormone deficiency (height -3.5 SDS at chronological age 5 years 8 months; low growth factors; bone age delay; growth velocity 4.4 cm/year (<3rd centile); and peak growth hormone levels of 1.7 and 4.7 ng/ml by clonidine and insulin provocative testing, respectively). Treatment with recombinant human growth hormone (0.3 mg/kg/week) resulted in a dramatic increase in growth velocity, increasing the height from -3.5 to -1.5 SDS over 2.3 years of therapy, indicative of an excellent response. Growth retardation is a known association in PPS: a condition that includes other midline facial defects. This case supports a role for GHD in the pathogenesis of the short stature observed in these children; demonstrates the efficacy of GH treatment; and further reinforces the relationship of pituitary anomalies with common congenital defects.     

Ligase IV syndrome can present with microcephaly and radial ray anomalies similar to Fanconi anaemia plus fatal kidney malformations

Ligase IV (LIG4) syndrome is a rare disorder of DNA damage repair caused by biallelic, pathogenic variants in LIG4. This is a phenotypically heterogeneous condition with clinical presentation varying from lymphoreticular malignancies in developmentally normal individuals to significant microcephaly, primordial dwarfism, radiation hypersensitivity, severe combined immunodeficiency and early mortality. Renal defects have only rarely been described as part of the ligase IV disease spectrum.We identified a consanguineous family where three siblings presenting with antenatal growth retardation, microcephaly, severe renal anomalies and skeletal abnormalities, including radial ray defects. Autozygosity mapping and exome sequencing identified a novel homozygous frameshift variant in LIG4, c.597_600delTCAG, p.(Gln200LysfsTer33), which segregated in the family. LIG4 is encoded by a single exon and so this frameshift variant is predicted to result in a protein truncated by 678 amino acids. This is the shortest predicted LIG4 protein product reported and correlates with the most severe clinical phenotype described to date. We note the clinical overlap with Fanconi anemia and suggest that LIG4 syndrome is considered in the differential diagnosis of this severe developmental disorder.     

Teicoplanin plus ciprofloxacin versus gentamicin plus piperacillin in the treatment of febrile neutropenic patients

Teicoplanin plus ciprofloxacin was compared with gentamicin plus piperacillin for the empirical treatment of fever in 80 neutropenic patients. A favourable response was seen in 78 % of patients receiving teicoplanin plus ciprofloxacin and in 49 % receiving gentamicin plus piperacillin (p<0.05). When microbiologically documented episodes were analysed separately, the response to teicoplanin plus ciprofloxacin was favourable in 81 % of patients whereas only 35 % responded favourably to gentamicin plus piperacillin (p=0.034). Gram-positive organisms accounted for 76 % of bacterial isolates,Staphylococcus epidermidis being the most common pathogen. Ten of 12 (83 %)Staphylococcus epidermidis infections resolved when treated with teicoplanin plus ciprofloxacin as compared with 2 of 8 (25 %) treated with gentamicin plus piperacillin. Teicoplanin is at least as effective as gentamicin plus piperacillin in the empirical treatment of febrile neutropenic patients and may be more effective in situations where gram-positive organisms are prevalent. The high incidence of gram-positive infections in our unit justifies the use of an agent with specific activity against gram-positive organisms in the first-line antibiotic regimen.