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Werner Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Differential diagnoses for Werner syndrome include atypical Werner syndrome (early age of onset at early 20s or earlier, faster rate of progression; normal WRN proteins, heterozygous pathogenic missense variants in LMNA in 15% of cases), mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL; progeroid features, lipodystrophy, characteristic facial features, sensorineural hearing loss; absence of ocular cataracts), mandibulo-acral dysplasia (MAD; short stature, type A lipodystrophy, loss of fat in the extremities but accumulation of fat in the neck and trunk, thin, hyperpigmented skin, partial alopecia, prominent eyes, convex nasal ridge, tooth loss, micrognathia, retrognathia, and short fingers; biallelic pathogenic variants in LMNA, and zinc metalloproteinase ZMPSTE24), Hutchinson−Gilford progeria syndrome (HGPS, progeria of childhood; accelerated aging, profound failure to thrive during the first year, characteristic facies, partial alopecia progressing to total alopecia, loss of subcutaneous fat, progressive joint contractures, bone changes, abnormal tightness and/or small soft outpouchings of the skin over the abdomen and upper thighs during the second to third year; severe atherosclerosis; death due to cardiac or cerebrovascular disease between age 6 and 20 years; average life span of approximately 14.6 years; autosomal dominant disorder due to LMNA pathogenic variant c.1824C>T), early-onset type 2 diabetes with secondary complications (mimicking some features of Werner syndrome), myotonic dystrophy type 1 or myotonic dystrophy type 2 (young adult-onset cataracts, muscle wasting in adults), scleroderma, mixed connective tissue disorders, and lipodystrophy (similar skin features), Charcot−Marie−tooth hereditary neuropathy or familial leg ulcers of juvenile onset (distal atrophy and skin ulcerations in the absence of other manifestations characteristic of Werner syndrome), Rothmund−Thomson syndrome (RTS; autosomal recessive disorder due to pathogenic variants in RECQL4), BLM (increased sister chromatid exchange; autosomal recessive disorder due to pathogenic variants in BLM), Li−Fraumeni syndrome (multiple cancers, absence of juvenile-onset cataracts, autosomal dominant disorder due to pathogenic variants in TP53), Flynn−Aird syndrome (cataracts, skin atrophy and ulceration; neurologic abnormalities), brachiooculofacial syndrome (premature graying in adults; strabismus, coloboma, and microphthalmia; dysmorphic facial features; autosomal dominant disorder due to TFAP2A pathogenic variants), SHORT syndrome (short stature, hyperextensibility, hernia, ocular depression, Rieger anomaly, and teething delay; progeria-like facies and lipodystrophy, type 2 diabetes mellitus, cataracts and glaucoma; autosomal dominant disorder due to pathogenic variants in PIK3R1 [1,18,19].
Phosphatidylinositol 3-kinase signaling and immune regulation: insights into disease pathogenesis and clinical implications
Published in Expert Review of Clinical Immunology, 2021
Tina Nguyen, Elissa K Deenick, Stuart G Tangye
APDS2 patients have heterozygous variants in PIK3R1, which disrupt the inhibitory function of p85, causing over-active PI3K signaling (Figure 2). From a clinical immunology perspective, it is difficult to distinguish APDS2 from APDS1. Akin to APDS1, the most commonly observed clinical manifestation in APDS2 is recurrent respiratory infections that are present from childhood. APDS2 patients also experience lymphadenopathy, splenomegaly, severe or persistent EBV/CMV infections, lymphoma, and autoimmunity [17,18,39,42–46]. A small number of APDS2 patients have received additional diagnoses of a separate disorder called SHORT syndrome (Short stature, Hyperextensibility of the joints, Ocular depression, Rieger anomaly of the eyes, Teething Delays), which involves growth retardation and metabolic disease features [42,45,47]. The typical genetic lesion in SHORT syndrome is heterozygous variants in the more distal exons of PIK3R1 [48–50], rather than the common splice variant that causes exon 11 splicing resulting in APDS2.