Identification of a novel mutation in RIPK4 in a kindred with phenotypic features of Bartsocas-Papas and CHAND syndromes.

Three children from an expanded consanguineous Kuwaiti kindred presented with ankyloblepharon, sparse and curly hair, and hypoplastic nails, suggestive of CHAND syndrome (OMIM 214350) that belongs to the heterogeneous spectrum of ectodermal dysplasias. After exclusion of pathogenic mutations in TP63 we performed homozygosity mapping, followed by exome sequencing of one affected individual. We initially identified three homozygous mutations in the linked region, located in PWP2, MX2 and RIPK4. Recently, mutations in RIPK4 have been reported in Bartsocas-Papas syndrome (OMIM 263650) that shows overlapping clinical symptoms with the phenotype observed in the affected individuals studied here. Subsequent analysis of affected and non-affected family members showed that mutation c.850G>A (p.Glu284Lys) in RIPK4 was in complete segregation with the disease phenotype, in accordance with an autosomal recessive inheritance pattern, thus supporting pathogenicity of this variant. Interestingly, however, our patients did not have cleft lip/palate, a common feature encountered in Bartsocas-Papas syndrome. Whereas in Bartsocas-Papas syndromes missense mutations are usually located within the serin/threonin kinase of RIPK4, the mutation detected in our family resides just outside of the kinase domain, which could explain the milder phenotype. Our data raise the question if CHAND syndrome indeed is a distinct entity. Alternatively, CHAND and Bartsocas-Papas syndrome might be allelic disorders or RIPK4 mutations could confer varying degrees of phenotypic severity, depending on their localization within or outside functionally important domains. Our findings indicate that making an accurate diagnosis based only on the prevailing clinical symptoms is challenging.

Alopecia and hypotrichosis as characteristic findings in Woodhouse-Sakati syndrome: report of a family with mutation in the C2orf37 gene.

Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive disorder characterized by alopecia, hypogonadism, diabetes mellitus, intellectual disability, sensorineural deafness, extrapyramidal signs, and low insulinlike growth factor 1 levels. Inter- and intrafamilial phenotypic variability have been reported. Mutations in the C2orf37 gene cause WSS. The present report describes the clinical signs and symptoms of three affected siblings from a consanguineous Bedouin family from Kuwait. Direct sequencing of the C2orf37 gene revealed that the c.436delC (p.Ala147Hisfs*9) mutation was present in a homozygous state in all affected siblings and in a heterozygous state in the parents and a healthy sister. Nine C2orf37 mutations causing WSS have been identified. This family shared the mutation reported earlier in Saudi families and families of Bedouin tribes from Qatar and Israel. No phenotypic or genotypic correlation has been observed. Despite the great phenotypic variability of WSS, hypotrichosis has been observed in all individuals with WSS reported. This condition has not been reported in the dermatologic literature. WSS should be included in the differential diagnosis of syndromic congenital hypotrichosis.

Selected variants of the melanocortin 4 receptor gene (MC4R) do not confer susceptibility to female pattern hair loss.

Female pattern hair loss (FPHL) is a common hair loss disorder in women with a complex mode of inheritance. Its etiopathogenesis is poorly understood. Widespread assumptions of overlapping susceptibility variants between FPHL and male pattern baldness (androgenetic alopecia) and a crucial role of androgens or distinct sexual steroid hormones in the development of FPHL could neither be clearly demonstrated nor completely excluded at the molecular level up to date. Interestingly, recent studies suggested an association of metabolic syndrome-including obesity, hyperlipidaemia, hypertension and diabetes mellitus type 2 or abnormally high fasting blood glucose-with FPHL. Of note, mutations in the melanocortin 4 receptor gene (MC4R) have been identified in patients with morbid obesity. Interestingly, this neuropeptide receptor has been detected amongst others in the dermal papilla of the hair follicle. As almost half of our FPHL patients of German origin present with adipositas and/or obesity, we hypothesized as to whether FPHL could be associated with variants of the MC4R gene. Thus, we genotyped a total of six variants from MC4R in our case-control sample comprising 245 UK patients of German and UK origin. However, based on our present study none of the genotyped MC4R variants displayed any significant association, neither in the overall UK and German samples nor in any subgroup analyses. In summary, these results do not point to an involvement of MC4R in FPHL.

Identification of an Alu-mediated 12.2-kb deletion of the complete LPAR6 (P2RY5) gene in a Turkish family with hypotrichosis and woolly hair.

Hypotrichosis is a rare form of progressive hair loss characterized by sparse and occasionally woolly hair that is curly and breaks easily. Disease-causing mutations in LIPH, LPAR6 and KRT74 have recently been identified. We describe a four-generation pedigree from Turkey following an autosomal recessive pattern, in which the four affected members had hypotrichosis and woolly hair. By sequencing LPAR6 and the use of SNP arrays, we revealed a homozygous loss of the entire LPAR6 gene in the affected individuals. We hypothesize that the 12-kb deletion resulted from illegitimate recombination secondary to slip-replication. The orientation of three Alu repeats around LPAR6 may have provoked the formation of a 'triple-barrel' structure during replication, thereby allowing strand slipping. This first report of complete LPAR6 loss expands the spectrum of known LPAR6 mutations and suggests a novel mechanism for this gene and for the formation of DNA rearrangements in general.