Complex postaxial polydactyly types A and B with camptodactyly, hypoplastic third toe, zygodactyly and other digit anomalies caused by a novel GLI3 mutation.

Polydactyly is a phenotypically and genetically highly heterogeneous limb malformation with preaxial and postaxial subtypes and subtypes A and B. Most polydactyly entities are associated with GLI3 mutation. We report on 10 affected individuals from a large Pakistani kindred initially evaluated as a possible new condition. The phenotype is postaxial polydactyly types A and B associated with zygodactyly, postaxial webbing of toes and additional features not previously reported for isolated polydactyly such as camptodactyly, hypoplasia of third toe, and wide space between hallux and second toe. Hypothesizing that the disorder could have resulted from a mutation in a novel gene responsible for polydactyly, we launched a genetic investigation. By linkage mapping and exome sequencing in the most severe case, we identified novel heterozygous frameshift mutation NM_000168.5 (GLI3): c.3635delG (p.(Gly1212Alafs*18)) but did not detect any other possibly deleterious mutation that could explain the unusual features of camptodactyly, hypoplasia of third toe and wide space between first and second toes. Our findings further expand the phenotypic variability of GLI3 polydactyly. We also present a review of GLI3-associated isolated limb anomalies, which indicates that GLI3 mutation leads primarily to two well-established polydactyly types: postaxial types A and B and crossed polydactyly type I. In addition, a variety of other minor digit anomalies generally accompany polydactyly, and there is no straightforward genotype-polydactyly phenotype correlation.

Phenotypic manifestation of congenital transverse amputation of autopod in Pakistani subjects.

Terminal transverse deficiency of forearm is a very rare limb malformation. Most of the cases have traumatic etiology and congenital presentation is less common. A series of six individuals with transverse deficiency through the hands is presented in this communication. The cases were congenital, morphologically similar and showed loss of four fingers, most often postaxial. The affected arm was reduced in size compared to the contralateral limb and there was distortion of palmer creases. All cases were sporadic and non-syndromic in nature. The characteristics of these cases were concordant with the symbrachydactyly type III or monodactylous type, when classified according to the scheme proposed by Blauth and Gekeler (1973). The malformation resulted in permanent quality-of-life impairment in these subjects and warrant prosthetic management. Detailed physical and phenotypic features of the patients have been presented.

Congenital constriction ring of limbs in subjects with history of maternal substance use.

Congenital Constriction Ring (CCR) is a rare malformation which manifests itself in the form of ring-like constrictive bands. Due to its heterogeneous nature, its etiology remains unclear. Here, we present a series of seven independent individuals afflicted with CCR, which primarily involved the digits. The phenotypic manifestations included terminal phalangeal reduction, anonychia, digit hypoplasia, and acrosyndactyly. Mesoaxial digits in hands and preaxial digits in feet were most frequently affected. Camptodactyly and clubfoot were witnessed in four and one subject, respectively. Curiously, mothers of six of these subjects revealed that they consumed copious amounts of Multani mitti(Fuller's clay) and/or Naswar(nonsmoke-tobacco), during their respective pregnancies. Maternal substance use during pregnancy is not an unusual practice, however, its relationship with CCR as pregnancy outcome remains unexplored. Case-control studies are warranted to elucidate the relationship between the exposure to these substances and the etiology of CCR and/or other limb defects in the offspring.

Study of non-syndromic thumb aplasia in six independent cases.

OBJECTIVES: To report on six independent and isolated cases demonstrating thumb aplasia as an essentially limb-specific phenotype. METHODS: The subjects were ascertained during 2011-2013 from six different geographic regions of Pakistan, and underwent detailed clinical and phenotypic examination. RESULTS: The affected arms of patients had complete absence of first digital rays, medial inclinations of second and fifth fingers, narrowing of palms, missing carpals, and shortening of zeugopod. All the subjects were presented with isolated and sporadic limb deficiencies, and five had no family history of limb or any other malformation. Parental consanguinity was denied in majority of the cases. We present detailed phenotypic manifestation of thumb apalsia in these subjects. CONCLUSION: Thumb aplasia markedly impairs the normal function of affected hand. Surgical procedures like pollicisation of the index finger should be employed to improve the quality of life of these subjects. There is so far no specific genetic factor known for isolated thumb aplasia, compromising an accurate genetic counseling. Collection of patients with similar phenotypic presentations could be useful in further molecular genetic investigations.

Congenital hypoplasia of first digital ray of hands as an isolated presentation in four subjects.

Congenital hypoplasia of thumb is rare malformation which is less likely to appear as an isolated entity. Four independent subjects exhibiting various grades of underdeveloped first digital ray were recruited. The affected autopods had narrow palms, medial or valgus inclinations of index fingers and thenar weakness, while the postaxial digits were least affected. According to the classification of hypoplastic thumb by Blauth and Schneider-Sickert (1981), the phenotypes were concordant with types 3 and 4. In one of the subjects there was contralateral preaxial polydactyly. All cases were sporadic and nonsyndromic and parental consanguinity was witnessed in two individuals. Recurrent appearance of similar phenotypes may suggest genetic etiologies which should be elucidated with the help of high-throughput genetic methods.