Ahmad S. Teebi

Charcot‐Marie‐Tooth disease and related neuropathies: Mutation distribution and genotype‐phenotype correlation

Charcot‐Marie‐Tooth disease (CMT) is a genetically heterogeneous disorder that has been associated with alterations of several proteins: peripheral myelin protein 22, myelin protein zero, connexin 32, early growth response factor 2, periaxin, myotubularin related protein 2, N‐myc downstream regulated gene 1 product, neurofilament light chain, and kinesin 1B. To determine the frequency of mutations in these genes among patients with CMT or a related peripheral neuropathy, we identified 153 unrelated patients who enrolled prior to the availability of clinical testing, 79 had a 17p12 duplication (CMT1A duplication), 11 a connexin 32 mutation, 5 a myelin protein zero mutation, 5 a peripheral myelin protein 22 mutation, 1 an early growth response factor 2 mutation, 1 a periaxin mutation, 0 a myotubularin related protein 2 mutation, 1 a neurofilament light chain mutation, and 50 had no identifiable mutation; the N‐myc downstream regulated gene 1 and the kinesin 1B gene were not screened for mutations. In the process of screening the above cohort of patients as well as other patients for CMT‐causative mutations, we identified several previously unreported mutant alleles: two for connexin 32, three for myelin protein zero, and two for peripheral myelin protein 22. The peripheral myelin protein 22 mutation W28R was associated with CMT1 and profound deafness. One patient with a CMT2 clinical phenotype had three myelin protein zero mutations (I89N+V92M+I162M). Because one‐third of the mutations we report arose de novo and thereby caused chronic sporadic neuropathy, we conclude that molecular diagnosis is a necessary adjunct for clinical diagnosis and management of inherited and sporadic neuropathy.

Genetic diversity among the Arabs.

The Arabs in general are genetically diverse. Major factors that contributed to their diversity include the migrations of Semitic tribes from the Arabian Peninsula, the Islamic expansion in the 7th century AD, the Crusade wars and the recent migration dynamics. These events have resulted in the admixture of the original Arabs with other populations extending from east and south Asia to Europe and Africa. Their demographic features include high rates of consanguinity, a large family size and a rapid population growth. There is a high frequency of autosomal recessive disorders and increased frequencies of homozygosity for autosomal dominant traits, such as familial hypercholesterolemia and X-linked traits, such as glucose-6-phosphate dehydrogenase deficiency. The patterns of autosomal recessive disorders, including their mutations, may be different in various geographic locations within the Arab world. However, there are disorders that are specifically prevalent among the Arabs either uniformly or in certain locations. The Arab Genetic diseases include Bardet-Biedl syndrome, Meckel syndrome, autosomal recessive severe childhood muscular dystrophy, osteopetrosis and renal tubular acidosis, Sanjad-Sakati syndrome and others.

Novel mutation in the gene encoding c-Abl-binding protein SH3BP2 causes cherubism.

Cherubism is a rare autosomal dominant inherited condition caused by mutations in the c‐Abl‐binding protein SH3BP2. It is characterized by multiple cystic giant cell lesions of the jaw appearing in early childhood with stabilization and remission after puberty. In the present study, we used direct sequence analysis of the SH3BP2 gene of several individuals from a family with cherubism to search for additional SH3BP2 mutations resulting in cherubism. In affected relatives, we found a previously unreported G to A transition in exon 9 leading to a Gly to Arg substitution at amino acid position 420. G420R has been reported previously with a G to C transversion. To date there have been no disease causing mutations outside exon 9. Therefore, the amino acid sequence from positions 415 to 420 may represent a specific protein domain which, when disrupted, leads to the cherubism phenotype.

Congenital heart defects in Sotos syndrome

Sotos syndrome is a relatively common overgrowth syndrome with characteristic physiognomy. We report on 3 patients with congenital heart defects out of 14 Sotos syndrome patients studied clinically and or by echocardiography. Review showed another 17 patients with variable cardiac defects, mostly closure defects, making an overall incidence of approximately 8%.

Bartsocas-Papas syndrome in an Arab family with four affected sibs: Further characterization

Bartsocas-Papas syndrome is a severe autosomal recessive popliteal pterygium syndrome. Other anomalies include microcephaly, facial clefts, filiform bands, ankyloblepharon, syndactyly, and other ectodermal and nonectodermal anomalies. We report on four Arab sibs with manifestations of this syndrome and some additional traits that include cutis aplasia, widely spaced nipples, low-set umbilicus, and unilateral renal hypoplasia among others. One was stillborn, and the other three children lived 10-17 months. Parents were nonconsanguineous, derived from different Bedouin tribes in Qatar and the United Arab Emirates. Similar cases from the literature are reviewed.

Structural central nervous system (CNS) anomalies in Kabuki syndrome

Kabuki make-up syndrome (KMS) [MIM147920] is a rare multiple congenital anomalies/mental retardation (MCA/MR) syndrome originally described by Niikawa et al. [1981] and Kuroki et al. [1981]. It is now well recognized worldwide with more than 400 cases reported in the literature [Armstrong et al., 2005; Schrander-Stumpel et al., 2005]. Most cases of KMS are sporadic, however several familial cases displayed autosomal dominant transmission [Tsukahara et al., 1997; Courtens et al., 2000]. KMS is characterized by a distinctive facial appearance, mild to moderate mental retardation, short stature, skeletal anomalies, and unusual dermatoglyphic patterns [Matsumoto et al., 2003]. The most striking feature is the peculiar face that consists of long palpebral fissures and long eyelashes, eversion of the lateral one-third of the lower eyelid, arched and notched eyebrows with sparseness of their lateral one-third, and prominent and anteverted ears. Since the facial appearance often reflects the developing brain, it is not unexpected to observe a relatively higher frequency of CNS anomalies compared with disorders with minimal facial dysmorphism.Anumber of reports have indicated an apparent increased frequency of suchanomalies.Herewereport on three unrelated patients with typical KMS and structural CNS anomalies and, briefly review literature pertaining to these anomalies in KMS patients.

Hypoparathyroidism, retarded growth and development, and dysmorphism or Sanjad-Sakati syndrome: an Arab disease reminiscent of Kenny-Caffey syndrome

Editor—In the December 1998 issue of Journal of Medical Genetics , four letters discussed whether or not Kenny-Caffey syndrome (KCS) is a part of CATCH 22.1-4 These were based on a report of four Bedouin sibs with an unusual form of KCS that includes the additional features of marked IUGR, severe psychomotor retardation, and microcephaly. Two of the affected sibs and their phenotypically normal mother were found to have microdeletion 22q11.5 The same authors subsequently suggested that this entity represents the Arab variant …

Reply to Ruiter et al.: A possible example of acrofacial dysostosis type Kennedy–Teebi

Ruiter et al. [2005] in their letter report a patient with craniofacial features resembling those reported recently by Kennedy and Teebi [2004]. These features are blepharophimosis, a peculiar beaked nose, low set dysplastic ear, malar hypoplasia, a long smooth philtrum, micrognathia, cleft palate, and relative microcephaly with OFC on 2nd centile and length on 40th centile at birth. Other features include arthrogryposis, presumably distal (not specified in their letter), with an absent left thumb and a hypoplastic right thumb. The authors suggest that their patient’s features are consistent with Nager syndrome (NS), mainly based on asymmetry of hand involvement, presence of cleft palate without cleft lip, and absence of microcephaly. In response to this I would like to stress the following: first, the absent thumb in one hand and a hypoplastic thumb in the other are clearly variable degrees of symmetric involvement; second, the presence of cleft palate without cleft lip is not uncommon in families where cleft lip and cleft palate are ascertained; and third, the patient’s relative microcephaly at birth, in the absence of a follow-up of head size (the patient died in early life), should not be ignored. Furthermore, it can not be considered normal to favor one diagnosis over the other. While NS is a very well delineated entity with more than 85 patients described [Gorlin et al., 2001], it is reasonable to consider the peculiar facial appearance and developmental delay in the cases reported by Kennedy and Teebi [2004] as differentiating features. This is in addition to the apparent pattern of autosomal recessive inheritance. It is possible that the patient seen by Ruiter et al. [2005] is another example of the Kennedy–Teebi type of acrofacial dysostosis, thus expanding the spectrum of this syndrome. Molecular characterization in the near future will be able to differentiate between NS and similar phenotypes.