Are triphalangeal thumb-polysyndactyly syndrome (TPTPS) and tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome (THPTTS) identical? A father with TPTPS and his daughter with THPTTS in a Thai family

We report on a Thai man who had triphalangeal thumb-polysyndactyly syndrome (TPTPS, MIM *190605) and his daughter who had tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome (THPTTS, MIM *188770). The father had polysyndactyly of triphalangeal thumbs, syndactyly of fingers, duplicated distal phalanx of the left great toe, brachymesophalangy of toes, and the absence of middle phalanges of some toes. He was diagnosed as having TPTPS. His daughter was more severely affected, having complete syndactyly of five-fingered hands in rosebud fashion (Haas-type syndactyly), hypoplastic tibiae, absent patellae, thick and displaced fibulae, preaxial polysyndactyly of triphalangeal toes, and cutaneous syndactyly of some toes, the manifestations being consistent with THPTTS. Having two different syndromes in the same family suggests that they are actually the same disorder. A literature survey showed that there have been several families where THPTTS occurred with TPTPS or Haas-type syndactyly (and/or preaxial polydactyly type 2, PPD2). In addition, all loci for TPTPS, THPTTS, and PPD2 (and/or PPD3) have been assigned to chromosome band 7q36. These findings support our conclusion that TPTPS, PPD2 (and/or PPD3), and Haas-type syndactyly are a single genetic en-tity (THPTTS). We propose to call the condition "tibial hemimelia-polysyndactyly-triphalangeal thumbs syndrome." Copyright 2000 Wiley-Liss, Inc.     

X‐linked mental retardation with alacrima and achalasia—Triple A syndrome or a new syndrome?

We describe a consanguineous Israeli Arab kindred with five males in two interrelated families with intellectual disabilities, alacrima, achalasia, and mild autonomic dysfunction. Adrenal function is normal. Their phenotype is similar to the phenotype observed in autosomal recessive Triple A syndrome except for the presence of mental retardation in all affected individuals. The pedigree is compatible with either X‐linked or autosomal recessive inheritance. Sequencing of the AAAS gene causing autosomal recessive Triple A syndrome did not reveal mutations. Genotyping of affected family members identified a 16.4 Mb continuous segment of identical alleles shared by the patients between markers rs2748314 and rs5906782 on Xp11.23‐p21, establishing linkage to chromosome X. This study further confirms genetic heterogeneity in Triple A syndrome and points to a clinically different subtype including significant cognitive impairment. © 2011 Wiley‐Liss, Inc.     

Branchial cyst,sensorineural deafness,congenital heart defect,and skeletal abnormalities: Branchio‐oto‐cardio‐skeletal (BOCS) syndrome?

This article describes a boy with an unusual combination of features, namely, intrauterine growth retardation, short stature, branchial cyst, sensorineural hearing loss, congenital heart defect, rib and vertebral abnormalities, micromelia, brachymesophalangia, and absence of phalanges. We suggest that these findings comprise a new entity of combined branchio‐oto and cardio‐digital developmental field abnormalities, which we termed branchio‐oto‐cardio‐skeletal syndrome. The pattern of inheritance remains uncertain. © 2002 Wiley‐Liss, Inc.     

Three‐year‐old girl with partial trisomy 4p and partial monosomy 8p with resemblance to Brachmann‐de Lange syndrome—another locus for Brachmann‐de Lange syndrome on 4p?

We describe a 3‐year‐old girl with partial trisomy 4p and partial monosomy 8p who had prenatal and postnatal growth retardation, mental retardation, no speech development, mild synophrys, hirsutism, apparently low‐set ears, dysphonic hoarse voice, hyperactivity, and small hands with proximal placement of the thumbs. She had recurrent lung infections, due to earlier aspiration and immune deficiency (chronic granulomatous disease). Cytogenetic findings in this and other cases with suggestive phenotype may point to an additional locus for Brachmann‐de Lange phenotype. Am. J. Med. Genet. 91:180–184, 2000. © 2000 Wiley‐Liss, Inc.     

First‐year growth in children with Noonan syndrome: Associated with feeding problems?

Children with Noonan syndrome show rapid decline of growth in the first year of life and feeding problems are present in over 50%. The aim of this study was to explore whether growth decelerates because of feeding problems or other Noonan syndrome‐related factors. We performed a retrospective, longitudinal cohort study of clinically and genetically diagnosed subjects with Noonan syndrome (n = 143). Questionnaires about the phenotypic–genotypic profile and reported feeding problems were sent to eligible subjects. Data on first‐year growth was obtained from growth charts. Ninety‐one participants were excluded because of different criteria. A total of 52 subjects with Noonan syndrome were included. The largest decline in weight and length standard deviation score (SDS) occurred in the first 2.5 months after birth (−1.93 and −1.15, respectively), with feeding problems causing a decline of 0.57 SDS in the remaining months. At 1 year, children with feeding problems were on average 290 g lighter and 0.8 cm shorter than children without feeding problems. Weight gain was also negatively influenced by having a PTPN11 mutation (n = 39) and a higher gestational age, whereas children of parents with Noonan syndrome and with a higher birth weight gained more weight. Growth in length was reduced by having cardiac surgery and a higher gestational age, but positively influenced by birth length and maternal height. Growth in children with Noonan syndrome is impaired right after birth and only partially associated with feeding problems. In addition, several specific Noonan syndrome‐related factors seem to influence growth in the first year.     

Can interferon‐γ and interleukin‐10 balance be associated with severity of human Leishmania (Viannia) braziliensis infection?

Suitable levels of interferon (IFN)-gamma and interleukin (IL)-10 seem to favour the outcome of cutaneous leishmaniasis (CL), while high IFN-gamma and low IL-10 production are associated with severity of mucosal leishmaniasis (ML). Considering that cytokine balance is important for the maintenance of protective responses in leishmaniasis, our aim was to investigate leishmanial antigens-induced IFN-gamma and IL-10 levels maintained in healed individuals who had different clinical outcomes of Leishmania infection. Thirty-three individuals who recovered from L. braziliensis infection were studied: cured CL (CCL), cured ML (CML), spontaneous healing of CL (SH) or asymptomatic individuals (ASY). Cytokines were quantified by enzyme-linked immunosorbent assay (ELISA) in culture supernatants of L. braziliensis-stimulated peripheral blood mononuclear cells (PBMC). IFN-gamma levels were higher in CML (7593 +/- 5994 pg/ml) in comparison to SH (3163 +/- 1526 pg/ml), ASY (1313 +/- 1048 pg/ml) or CCL (1897 +/- 2087 pg/ml). Moreover, cured ML cases maintained significantly lower production of IL-10 (127 +/- 57.8 pg/ml) in comparison to SH (1373 +/- 244 pg/ml), ASY (734 +/- 233 pg/ml) or CCL (542 +/- 375 pg/ml). Thus, a high IFN-gamma/IL-10 ratio observed in CML can indicate unfavourable cytokine balance. On the other hand, no significant difference in the IFN-gamma/IL-10 ratio was observed when CCL individuals were compared to SH or ASY subjects. In conclusion, even after clinical healing, ML patients maintained a high IFN-gamma/IL-10 secretion profile in response to leishmanial antigens. This finding can explain a delayed down-modulation of exacerbated inflammatory responses, which can be related in turn to the necessity of prolonged therapy in ML management. Conversely, lower IFN-gamma/IL-10 balance observed in CCL, SH and ASY individuals can represent a better-modulated immune response associated with a favourable prognosis.     

Are Noonan syndrome and Noonan‐like/multiple giant cell lesion syndrome distinct entities?

We report on a family with typical clinical findings of Noonan syndrome associated with giant cell lesions in maxilla and mandible.We discuss the obvious clinical overlap between Noonan syndrome and Noonan‐like/multiple giant cell lesion syndrome, and we give further clinical and molecular support that these two entities could be allelic conditions. © 2001 Wiley‐Liss, Inc.     

Klippel‐Feil anomaly with Sprengel anomaly,omovertebral bone,thumb abnormalities,and flexion‐crease changes: Novel association or syndrome?

We report on a family with Klippel‐Feil anomaly (KF), Sprengel anomaly, omovertebral bone, thumb abnormalities, and flexion‐crease abnormalities. This combination of abnormalities does not fit into Holt‐Oram syndrome, Wildervanck syndrome, oculo‐auriculo‐vertebral (Goldenhar) anomaly, or the VATER complex. Clinical aspects of a KF classification are discussed. The state of molecular research on KF is briefly reported. We conclude that this set of anomalies is a novel combination, probably representing pleiotropy of a single Mendelian gene. © 2001 Wiley‐Liss, Inc.     

Crohn's disease associated with Sweet's syndrome and Sjögren's syndrome treated with infliximab

The association of Crohn''s disease (CD) and Sweet''s syndrome is rare and the presence of Sjögren''s syndrome in Crohn''s disease is even rarer, with only three reports found in the literature. We describe two cases of Crohn''s disease associated with Sweet''s syndrome, one of which is the first case of CD and Sweet''s concomitantly associated with Sjögren''s syndrome. Both cases responded rapidly to Infliximab therapy with complete resolution of the skin lesions.     

Clinical and laboratory features of seventy-eight UK patients with Good’s syndrome (thymoma and hypogammaglobulinaemia)

Good’s syndrome (thymoma and hypogammaglobulinaemia) is a rare secondary immunodeficiency disease, previously reported in the published literature as mainly individual cases or small case series. We use the national UK-Primary Immune Deficiency (UKPID) registry to identify a large cohort of patients in the UK with this PID to review its clinical course, natural history and prognosis. Clinical information, laboratory data, treatment and outcome were collated and analysed. Seventy-eight patients with a median age of 64 years, 59% of whom were female, were reviewed. Median age of presentation was 54 years. Absolute B cell numbers and serum immunoglobulins were very low in all patients and all received immunoglobulin replacement therapy. All patients had undergone thymectomy and nine (12%) had thymic carcinoma (four locally invasive and five had disseminated disease) requiring adjuvant radiotherapy and/or chemotherapy. CD4 T cells were significantly lower in these patients with malignant thymoma. Seventy-four (95%) presented with infections, 35 (45%) had bronchiectasis, seven (9%) chronic sinusitis, but only eight (10%) had serious invasive fungal or viral infections. Patients with AB-type thymomas were more likely to have bronchiectasis. Twenty (26%) suffered from autoimmune diseases (pure red cell aplasia, hypothyroidism, arthritis, myasthenia gravis, systemic lupus erythematosus, Sjögren’s syndrome). There was no association between thymoma type and autoimmunity. Seven (9%) patients had died. Good’s syndrome is associated with significant morbidity relating to infectious and autoimmune complications. Prospective studies are required to understand why some patients with thymoma develop persistent hypogammaglobulinaemia.     

Spatial separation of endothelial small‐ and intermediate‐conductance calcium‐activated potassium channels (KCa) and connexins: possible relationship to vasodilator function?

Activation of endothelial cell small‐ (S) and intermediate‐ (I) conductance calcium‐activated potassium channels (K_Ca) and current or molecular transfer via myoendothelial gap junctions underlies endothelium‐derived hyperpolarization leading to vasodilation. The mechanism underlying the K_Ca component of vasodilator activity and the characteristics of gap junctions are targets for the selective control of vascular function. In the rat mesenteric artery, where myoendothelial gap junctions and connexin (Cx) 40 are critical for the transmission of the endothelial cell hyperpolarization to the smooth muscle, SK_Ca and IK_Ca provide different facets of the endothelium‐derived hyperpolarization response, being critical for the hyperpolarization and repolarization phases, respectively. The present study addressed the question of whether this functional separation of responses may be related to the spatial localization of the associated channels? The distribution of endothelial SK_Ca and IK_Ca and Cx subtype(s) were examined in the rat mesenteric artery using conventional confocal and high‐resolution ultrastructural immunohistochemistry. At the internal elastic lamina–smooth muscle cell interface at internal elastic lamina holes (as potential myoendothelial gap junction sites), strong punctate IK_Ca, Cx37 and Cx40 expression was present. SK_Ca, Cx37, Cx40 and Cx43 were localized to adjacent endothelial cell gap junctions. High‐resolution immunohistochemistry demonstrated IK_Ca and Cx37‐conjugated gold to myoendothelial gap junction‐associated endothelial cell projections. Clear co‐localization of K_Ca and Cxs suggests a causal relationship between their activity and the previously described differential functional activation of SK_Ca and IK_Ca. Such precise localizations may represent a selective target for control of vasodilator function and vascular tone.     

Diagnosis and classification of eosinophilic granulomatosis with polyangiitis (formerly named Churg–Strauss syndrome)

Recently, a group of experts in the field suggested to rename Churg–Strauss syndrome as eosinophilic granulomatosis with polyangiitis (EGPA). This condition, first described in 1951, is a rare small- and medium-sized–vessel vasculitis characterized by an almost constant association with asthma and eosinophilia, and, by the presence of anti-myeloperoxidase (MPO) antineutrophil cytoplasm antibodies (ANCA) in 30–38% of the patients. Vasculitis typically develops in a previously asthmatic and eosinophilic middle-aged patient. Asthma is severe, associated with eosinophilia and extrapulmonary symptoms. Most frequently EGPA involves the peripheral nerves and skin. Other organs, however, may be affected and must be screened for vasculitis, especially those associated with a poorer prognosis, such as the heart, kidney and gastrointestinal tract, as assessed by the recently revised Five-Factor Score (FFS). Recent insights, particularly concerning clinical differences associated with ANCA status, showed that EGPA patients might constitute a heterogeneous group. Thus, EGPA patients with anti-MPO ANCA suffered more, albeit not exclusively, from vasculitis symptoms, such as glomerulonephritis, mononeuritis multiplex and alveolar hemorrhage, whereas ANCA-negative patients more frequently develop heart involvement. This observation led to the hypothesis that EGPA might be divided into different clinical and pathophysiological subtypes, which could be managed better with more specifically adapted therapies.For now, EGPA treatment still relies mainly on corticosteroids and, when necessary for patients with poorer prognoses, combined immunosuppressant drugs, especially cyclophosphamide. Overall survival of EGPA patients is good, despite not uncommon relapses.     

Ventricular noncompaction and absent thumbs in a newborn with tetrasomy 5q35.2‐5q35.3: An association with Hunter–McAlpine syndrome?

We report on an infant with tetrasomy of 5q35.2-5q35.3, an interstitial triplication on one chromosome and normal complement on the other. The patient has some features of Hunter-McAlpine syndrome including intrauterine growth retardation (IUGR), almond-shaped eyes, epicanthal folds, and downturned mouth with thin vermillion of the upper lip. In addition, left ventricular noncompaction and absent thumbs were identified, which have never been described in Hunter-McAlpine syndrome. This chromosome abnormality is distinct from those previously reported. Within this region of tetrasomy is MSX2, a highly conserved homeobox containing gene. Increased copies of MSX2 have been previously associated with craniosynostosis. Our patient's only skeletal defect is absent thumbs, also potentially related to increased dosage of MSX2 which is important for limb formation. In addition, MSX2 is expressed in the developing heart and overexpression of this gene may disrupt the co-regulation of other cardiac genes in this region, namely CSX1.     

Jeune syndrome with tongue lobulation and preaxial polydactyly,and Jeune syndrome with situs inversus and asplenia: Compound heterozygosity Jeune-Mohr and Jeune-Ivemark?

We report on a male infant with internal hydrocephalus, absence of corpus callosum, papillomas and lobulation of the tongue, notches of the alveolar ridges, short ribs, dysplastic pelvis, hypospadias, short limbs with bowed long tubular bones and postaxial polydactyly of hands, and preaxial polydactyly in one foot. Radiologically this case shares manifestations with Jeune syndrome; the tongue lobulation and the preaxial polydactyly are similar to findings in Mohr syndrome, or short-rib polydactyly syndrome (SRPS), type Majewski. In addition, a female newborn presented with manifestations of Jeune and Ivemark syndromes. One explanation for this overlap may be compound heterozygosity for these syndromes. © 1996 Wiley-Liss, Inc.     

Post‐CPAP sleepiness – a specific syndrome?

Following treatment with continuous positive airway pressure (CPAP), some patients with obstructive sleep apnoea (OSA) remain sleepy despite effective CPAP and attention to other diagnoses that can provoke sleepiness. It is unclear if this residual sleepiness is an irreversible result of their previous OSA and merits consideration for pharmacological treatment or simply because of the many and varied causes of sleepiness normally found in the community. We have measured levels of sleepiness, using the Epworth Sleepiness Score (ESS), in 572 patients on CPAP and compared them with a control group of 525 subjects from a community survey, which would have included the usual lifestyle reasons for sleepiness as well as any undiagnosed sleep disorders. There was no difference in the percentage of patients with an ESS >10 in the CPAP group compared with the controls (16.1 versus 14.3, P = 0.54). Thus, although there clearly are sleepy patients within the CPAP group, the prevalence is no higher than in the community. We question whether so-called 'post-CPAP sleepiness' should be regarded as any more abnormal and worthy of treatment than a 'normal' population. Post-CPAP sleepiness as a specific disorder may not exist.     

Retinitis pigmentosa in a young man with Noonan syndrome: Further evidence that Noonan syndrome (NS) and the cardio-facio-cutaneous syndrome (CFC) are variable manifestations of the same entity?

We report on a young man with Noonan syndrome (NS) and retinitis pigmentosa. As far as we know, retinitis pigmentosa has not been reported in NS. However, in the 3 cardio-facio-cutaneous syndrome (CFC) patients in whom electroretinographic studies were performed, retinal anomalies have been found. In addition, decreased vision, refractive errors, strabismus, and optic disc anomalies were reported in CFC patients. This observation suggests that NS and CFC are variable manifestations of the same entity. © 1996 Wiley-Liss, Inc.     

Syndiotactic Poly(propylene) from [Me2Si(3,6‐di‐tert‐butyl‐9‐fluorenyl)(N‐tert‐butyl)]TiCl2–Based Catalysts: Chain‐End or Enantiotopic‐Sites Stereocontrol?

The origin of the syndiotactic selectivity in propene polymerization of a typical bridged fluorenyl‐amido catalyst, namely [Me₂Si(3,6‐di‐tert‐butyl‐9‐fluorenyl)(N‐tert‐butyl)]TiCl₂ ( 1 ), activated with methylaluminoxane or [HMe₂N(C₆H₅)][B(C₆F₅)₄]/Al(i‐butyl)₃, was investigated by means of 150 MHz ¹³C NMR spectroscopic microstructural polymer analysis. The asymmetric induction was traced unambiguously to enantiotopic‐sites control. Compared with the better‐known cyclopentadienyl‐fluorenyl ansa‐zirconocenes, 1 turned out to be almost identically enantioselective (in agreement with computer modeling), but less stereoselective because of a higher propensity to undergo site epimerization. This results in a chain microstructure with large predominance of m over mm stereodefects, deceptively similar to that of syndiotactic poly(propylene) produced under chain‐end control.

Methyl region of the 150 MHz ¹³C NMR spectrum of a poly(propylene) sample prepared with catalyst system 1 /borate/TIBAl.