Study On Clinical Features And Molecular Genetics Of Autosomal Recessive Hereditary Hypotrichosis

Background Hypotrichosis simplex （HS） is a group of non-syndromic humanhereditary hair loss disorders with clinical and genetic heterogeneity. The hair loss isdiffuse and progressive, and usually begins in early childhood. It can be inherited in anautosomal dominant or recessive mode. Autosomal recessive hypotrichosis simplex（ARHS） comprises five forms in which three forms （LAH1, LAH2and LAH3） arecaused by mutations in DSG4, LIPH and LPAR6gene, respectively. Two forms areassociated with chromosome10q11.23-q22.3and7p22.3-p21.3. Hereditary woolly hair（WH） is a group of rare hair shaft disorders characterized by fine and tightly curled hairsince birth, which can lead to hair depigmentation and hypotrichosis later in life. It canbe classified into syndromic form and non-syndromic form. The isolated form istransmitted as either an autosomal recessive or dominant trait. The mutations in LIPH orLPAR6are responsible for LAH2, LAH3and autosomal recessive woolly hair with orwithout hypotrichosis （ARWH/HT）.Objective （1） To conduct clinical and genetic investigations in three unrelated ChineseHan families with ARHS and a consanguineous Chinese Han family with ARWH/HT.（2）To summarize the genotype-phenotype correlation in ARHS and ARWH/HT.Methods We carried out survey in genetics and physical examination in three ARHSpatients and one ARWH/HT patient. Hairs and blood samples were collected frompatients and their families for scanning electron microscopy examination and mutationanalysis, respectively, after informed consent obtained. Two hundred unrelated bloodsamples from healthy individuals were collected as controls. Genomic DNA was extracted by using Qiagen FlexiGene DNA kit. We amplified all exons and exon-intronboundaries of DSG4, LPAR6and LIPH gene by polymerase chain reaction （PCR） anddirectly sequenced the purified PCR products by ABIPRISM3730XL automatedsequencer. We summarized clinical features and gene mutations in patients with ARHSand ARWH/HT in all published literatures to explore the genotype-phenotypecorrelation.Results （1） All three patients with ARHS presented as sparse scalp hairs at birthfollowed by extremely slow hair growth. Physical examination revealed diffusely sparse,thin, and short hair on their scalps. Moreover, two patients also had mild sparseeyebrows, while other patient showed complete absence of axillary hairs and pubic hairs.However, their teeth, nails, palms, soles and mental development were normal. SEM ofhairs revealed that variable peeling of cuticles occurred in their hair shaft. In addition,slight torsion, marked rough appearance and a few small holes appeared in one case.The patient with ARWH/HT showed diffusely sparse, coarse and curly scalp hairs aswell as sparse beards, complete absence of axillary hairs. His eyebrows, eyelashes orpubic hairs were normal. His teeth, nails, palms, soles and mental development werealso normal. SEM of hairs revealed slight torsion, flattening, longitudinal grooves andsevere peeling of cuticles of hair shaft.（2） Direct sequencing analysis of LIPH generevealed a homozygous missense mutation （c.742C>A; p.H248N） in one of threepatients with ARHS. Neither of mutations in DSG4or LPAR6gene was detected. Anovel homozygous deletion mutation （c.328₃30delATT; p.Ile110del） in LPAR6wasidentified in a patient with ARWH/HT. His parents and younger sister carried aheterozygous mutation in LPAR6. No mutation in LIPH gene was found. Thesemutations were not detected in200unrelated healthy controls.（3） There was not a clearcorrelation between genotype and clinical phenotype in ARHS or ARWH/HT. Conclusion （1） ARHS is clinically characterized by onset of sparse hairs at birth,extremely slow hair growth and diffusely sparse, thin and short scalp hairs with normal,scarce or absent eyebrows, eyelashes, beards, axillary hairs or pubic hairs. Variablepeeling of cuticles and normal shape in hair shaft are the significant ultrastructuralfindings of ARHS. ARWH/HT is clinically characterized by diffusely sparse, coarseand curly scalp hairs with variable involvement of beards and axillary hairs. Severepeeling of the cuticles and irregular longitudinal grooves in hair shaft are typical of thisdisease.（2） A homozygous missense mutation （c.742C>A） and a homozygous deletionmutation （c.328₃30delATT） respectively underlie ARHS and ARWH/HT. Our findingsprovide a basis for further genetic counseling and prenatal gene diagnosis in thesefamilies.（3） There was not a clear correlation between genotype and clinical phenotypein ARHS or ARWH/HT.