Dermatol Ther (Heidelb) (2019) 9:421–448 https://doi.org/10.1007/s13555-019-0313-2 REVIEW Genetic Hair Disorders: A Review Azhar Ahmed . Hind Almohanna . Jacob Griggs . Antonella Tosti Received: April 1, 2019 / Published online: July 22, 2019 Ó The Author(s) 2019 ABSTRACT physical examination of hair and other ecto- dermal structures such as nails, sweat glands, Hair loss in early childhood represents a broad and sebaceous glands with the use of dermo- differential diagnosis which can be a diagnostic scopic devices and biopsy all provide important and therapeutic challenge for a physician. It is clues to establish the correct diagnosis. Under- important to consider the diagnosis of a genetic standing the pathophysiology of genetic hair hair disorder. Genetic hair disorders are a large defects will allow for better comprehension of group of inherited disorders, many of which are their treatment and prognosis. For example, in rare. Genetic hair abnormalities in children can patients with an isolated hair defect, the main be an isolated phenomenon or part of genetic problem is aesthetic. In contrast, when the hair syndromes. Hair changes may be a significant defect is associated with a syndrome, the prog- finding or even the initial presentation of a nosis will depend mainly on the associated syndrome giving a clue to the diagnosis, such as condition. Treatment of many genetic hair dis- Netherton syndrome and trichothiodystrophy. orders is focused on treating the primary cause Detailed history including family history and and minimizing trauma to the hair. Keywords: Alopecia; Children; Ectodermal Enhanced Digital Features To view enhanced digital features for this article go to https://doi.org/10.6084/ dysplasias; Genetic hair disorders; Hair loss; m9.figshare.8578415. Hair shaft disorders; Hypotrichosis A. Ahmed Department of Dermatology, King Fahad General INTRODUCTION Hospital, Medina, Saudi Arabia H. Almohanna Hair is a skin appendage that shares a common Department of Dermatology and Dermatologic developmental pathway with other ectodermal Surgery, Prince Sultan Military Medical City, tissue [1]. Human hair is a key phenotypic Riyadh, Saudi Arabia indicator of possible underlying metabolic or A. Ahmed (&) Á J. Griggs Á A. Tosti genetic syndromes. Department of Dermatology and Cutaneous Genetic hair disorders can cause severe Surgery, University of Miami Miller School of alopecia in both adults and children and may Medicine, University of Miami Hospital, Miami, FL, occasionally present as part of a multisystem USA e-mail: [email protected] syndrome. So, the diagnosis of these genetic 422 Dermatol Ther (Heidelb) (2019) 9:421–448 disorders is important not only for the initia- HYPOTRICHOSIS tion of proper therapy but also for the detection of other associated ectodermal anomalies and In hypotrichosis, sparse hair is the result of a for appropriate genetic counselling. Affected hair regeneration defect, caused by impairment children and their parents are usually psycho- in hair cycling and anchoring of the hair shaft logically impacted by such conditions. in the skin [2]. Mutations in different genes In this review we summarize the main have been associated with non-syndromic as genetic hair disorders and discuss the clinical well as syndromic forms [3], including features, known associated genetic abnormali- hypotrichosis simplex, hypotrichosis with ties, and current treatment modalities. The juvenile macular dystrophy (HJMD), Marie review will focus on hypotrichosis, hair shaft Unna hypotrichosis (MUH), and autosomal disorders (with and without increased fragility), recessive woolly hair/hypotrichosis simplex. and ectodermal dysplasia. Table 1 summarize the gene defect, clinical presentation, and Hypotrichosis Simplex treatment tried for each genetic hair disorder. Hypotrichosis simplex (HS) (Mendelian Inheri- METHODS tance in Man (MIM) 146520, MIM 278150, MIM 146550, MIM 613981, and MIM 605389) [4]isa We searched keywords using PubMed and descriptive term for the clinical manifestations Medline to identify all relevant publications. related to diffuse hair thinning without any The terms ‘‘Hair loss,’’ ‘‘Alopecia,’’ ‘‘Hypotri- morphological abnormalities of the hair shaft. chosis,’’ ‘‘Trichorrhexis nodosa,’’ ‘‘Trichorrhexis Several hereditary hypotrichosis simplex (HHS) invaginate,’’ ‘‘Bamboo hair,’’ ‘‘Pili torti,’’ ‘‘Tri- pedigrees have been published showing auto- chothiodystrophy,’’ ‘‘Monilethrix,’’ ‘‘Pili annu- somal dominant inheritance, while others show lati,’’ ‘‘Woolly hair,’’ ‘‘Uncombable hair autosomal recessive inheritance. Clinical vari- syndrome,’’ ‘‘Pili trianguli et canaliculi,’’ ‘‘Ecto- ability can be observed on the basis of patient’s dermal dysplasias,’’ ‘‘Trichorhinophalangeal age of onset, as well as eyebrow and eyelash syndrome,’’ ‘‘pediatric,’’ ‘‘congenital,’’ ‘‘genetic,’’ involvement [5]. Mutations in six genes have and ‘‘children’’ were included as a search terms been identified for isolated HS, and mutations to identify all relevant publications. in three of them—CDSN (MIM 602593), Three independent researchers performed a APCDD1 (MIM 607479), and RPL21 (MIM literature search to identify all relevant studies. 603636)—are responsible for autosomal domi- Only published articles written in English were nant forms [4]. chosen. A total of 159 articles within the last When the hypotrichosis simplex is only 50 years were selected to be included in this limited to the scalp, it is called hereditary review. hypotrichosis simplex of the scalp (HHSS) (MIM All procedures followed were in accordance 146520), which is a rare non-syndromic auto- with the ethical standards of the responsible somal dominant condition characterized by committee on human experimentation (insti- exclusively scalp hair loss, sparing other ecto- tutional and national) and with the Helsinki dermal structures and with no systemic abnor- Declaration of 1964, as revised in 2013. This malities [6]. It is caused by nonsense mutations article is based on previously conducted studies in the corneodesmosin gene (CDSN) which and does not contain any studies with human leads to expression of a truncated protein participants or animals performed by any of the probably toxic to hair growth [7]. authors. Tables/figures are original and have Patients present with normal hair at birth, been produced by the authors for this particular then a gradually progressive scalp hair loss publication. The authors have consent from the begins in the middle of the first decade ending patients for using their images in this with almost complete hair loss by the third publication. decade. Eyebrows, eyelashes, and other body Table 1 Summary table of gene defect, clinical presentation, and treatment of genetic hair disorders Dermatol Ther (Heidelb) (2019) 9:421–448 Tag Genetic defect Hair finding Other clinical findings Light or electron Treatment microscopy, or Trichoscopic finding Hypotrichosis Hereditary AD Exclusively scalp hair Other ectodermal structures Wiry, twisted scalp hair, Unsatisfactory hypotrichosis simplex Nonsense lossEyebrows, eyelashes, are normal and with no resembling PT Topical minoxidil can of the scalp mutations in the and other body hair are systemic abnormalities improve the hair density CDSN gene completely norma and texture Marie Unna AD. Normal to adequate hairs at Nails, teeth, and sweat glands Wearing wig is the best hypotrichosis Mutation of the birth then develop pattern are normal. Milia-like option U2HR gene, alopecia at puberty. facial lesions can occur located in Eyelashes, eyebrows, body chromosome hair and secondary sexual 8p21 hair are sparse Autosomal recessive Mutation inMor Since infancy sparse, coarse, woolly hair/ lipase dry, and tightly curled hair, hypotrichosis simplex membrane H usually blond or lighter gene than other family members. Hypotrichosis with AR Early hair loss, heralding Progressive degeneration of Light and scanning juvenile macular Gene defective in progressive degeneration of the retinal macula leading electron microscopy dystrophy to 16q22.1. This the retinal macula to early blindness during of the hair shaft region contains the second to third decade revealed PT CDH3, of life encoding P-cadherin 423 424 Table 1 continued Tag Genetic defect Hair finding Other clinical findings Light or electron Treatment microscopy, or Trichoscopic finding Hair Shaft Disorders with Increases Fragility Arginosuccinic aciduria Deficiency of Normal hair at birth but Failure to thrive and mental TN Managing the underlying arginosuccinic then develop TN retardation. disorder lyase Zinc sulfate 45mg/day and Citrullinemia Deficiency of Abnormally fragile hair with TN 50 mg/day was tried arginosuccinate TN – synthetase Netherton syndrome AR mutations in short sparse fragile hair with CIE or ILC, atopic athesis TI Treatment is aimed to deal the SPINK5 TI (elevated di IgE) with the skin findings of gene Netherton syndrome more than the hair abnormality, and may include low dose oral steroids, etretinate,psoralen ultraviolet A therapy, topical tacrolimus, and lactate lotion 12% Dermatol Ther (Heidelb) (2019) 9:421–448 Dermatol Ther (Heidelb) (2019) 9:421–448 Table 1 continued Tag Genetic defect Hair finding Other clinical findings Light or electron Treatment microscopy, or Trichoscopic finding Monilethrix AD (KRT81 , Normal hair at birth replaced keratosis pilaris, koilonychia, Light microscopy shows systemic retinoid therapy KRT83, and by dull brittle hair.it retarded growth and typical beaded or where etretinate at 0.5 KRT86 gene commonly