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Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Published in Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow, Fetal and Perinatal Skeletal Dysplasias, 2012
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow
Many other syndromes can have SHFM within their spectrum, including a number of chromosomal anomalies, such as trisomies 13 and 18 (pp. 582, 586), and partial trisomies or monosomies scattered through many chromosomal loci. Patterson-Stevenson-Fontaine syndrome also shows mandibulofacial dysostosis. Ulnar-mammary syndrome: shows posterior limb defects, hypoplasia of mammary gland, abnormal dentition, and genital anomalies; caused by dominant mutations in TBX3. Adams-Oliver syndrome: transverse limb defects associated with aplasia cutis, usually limited to the scalp vertex, occasionally presents with vascular defects and cardiac malformations. Cenani-Lenz syndactyly syndrome: also called ‘total syndactyly’, shows a total fusion of fingers and toes, extensive fusion of carpals and metacarpals with single, partial or complete radioulnar synostosis, brachymesomelia; due to recessive mutations in LRP4. Tibial aplasia with SHFM: also shows bilateral aplasia of the tibiae, distal hypoplasia or bifurcation of femora, aplasia or hypoplasia of ulnae, aplasia of patellae; maps to chromosomes 1q42.2-q43, 6q14.1 and 17p13.3. Recently a predisposing microduplication encompassing BHLHA9 on 17p13.3 has been described. Cornelia de Lange syndrome (p. 454); CCGE (Cleft palate, Cardiac defect, Genital anomalies, Ectrodactyly): a very rare and severe disorder, brain anomalies can be present, early lethality has been reported in the few described cases. Goltz syndrome: the hallmark is focal dermal hypoplasia, which can be extensive and spreads on all the body surface; associated features include ocular anomalies (coloboma of iris and choroid, microphthalmia), hypoplastic teeth, striated bones, cardiac malformations and intellectual impairment. X-linked dominant, caused by mutations in PORCN; lethal in utero in males. SHFM has also been reported in severe cases of Smith–Lemli–Opitz syndrome and VACTERL association (p. 590); in these cases the multiple malformation pattern is striking and usually allows the correct diagnosis to be made.
The Notch pathway: a novel therapeutic target for cardiovascular diseases?
Published in Expert Opinion on Therapeutic Targets, 2019
Giorgio Aquila, Aleksandra Kostina, Francesco Vieceli Dalla Sega, Eugeniy Shlyakhto, Anna Kostareva, Luisa Marracino, Roberto Ferrari, Paola Rizzo, Anna Malaschicheva
NOTCH1 and JAG1 mutations have been associated with Tetralogy of Fallot (TOF), a severe developmental CHD [40], characterized by stenosis of right ventricular OFT, ventricular septal defect, dextraposition of aorta and right ventricular hypertrophy. A recent study of whole exome sequencing in 829 TOF patients has shown that the NOTCH1 locus is the most frequent site of genetic variants predisposing to nonsyndromic TOF [41]. Mutations in NOTCH1 are also associated with hypoplastic left heart syndrome, a defect in which the left side of the heart is underdeveloped [42] and with the Adams-Oliver syndrome (AOS), a rare congenital disease characterized by cardiac, vascular and neurological symptoms, including valvular and ventricular abnormalities, atrial septal defect, and TOF [43]. In AOS have been also found mutations in RBPJ and DLL4 [43] and in EOGT, encoding an EGF domain-specific O-linked N-acetylglucosamine transferase which presumably could regulate Notch receptors [44].
Current opinion in the molecular genetics of Adams-Oliver syndrome
Published in Expert Opinion on Orphan Drugs, 2019
First described by Forrest H. Adams and Clarence P. Oliver in 1945 as ‘arrested development’ of the extremities and skull, Adams–Oliver syndrome (AOS) is distinct from congenital amputations due to its Mendelian inheritance pattern and association with a characteristic focal absence of epidermis on the scalp vertex [1]. The family in this original case report epitomizes an important feature of the condition, namely variable expression of the phenotype within families. Terminal transverse limb defects (TTLD) is typically asymmetrical and can range in severity from mild digit shortening to complete absence of the hands or feet. Brachydactyly, syndactyly, and hemimelia have also been documented [1,2]. Similarly, aplasia cutis congenita (ACC) varies in diameter from <1 to >10 cm and can occur with or without an underlying skull defect. Both TTLD and ACC may manifest as isolated defects and a complete absence of clinical features in obligate gene carriers supports reduced penetrance of the disease allele, representing a diagnostic challenge. Given such variability in phenotypic expression, the following criteria are recommended as compatible with a diagnosis of AOS: (a) clinical findings of a combination of scalp ACC and TTLD; (b) ACC and/or TTLD and an affected first-degree relative; (c) ACC and/or TTLD in conjunction with identified mutation in a recognized AOS-related gene (Table 1) [2].
A novel variant in DOCK6 gene associated with Adams–Oliver syndrome type 2
Published in Ophthalmic Genetics, 2020
Tariq Alzahem, Abrar K. Alsalamah, Marco Mura, Sulaiman M. Alsulaiman
Adams–Oliver syndrome is classically characterized by a combination of ACC and TTLDs. Based on the diagnostic criteria proposed by Lehman in 2016 (13), a diagnosis of AOS is established when there is an ACC or TTLDs with biallelic pathogenic variants in an autosomal recessive AOS-related gene. Thus, although our patient did not have ACC, a diagnosis of AOS type 2 was reached based on the presence of TTLDs and the identification of a (likely) pathogenic homozygous variant in the DOCK6 gene.