doi:10.1684/ejd.2015.2529 C eCihCHEN WenChieh J,vl 5 n 25, vol. EJD, 16/1/2015 on accepted Article Reprints: 2 1 HAPPLE Rudolf RING Johannes Review 90 riug Germany Freiburg, 79104 7, Hauptstr. Center, Medical University Germany Munich, 80802 29, Biedersteinerstr. München, Universität Technische n -ikdpten ftasiso aebe reported, been have transmission of skin. dominant patterns the autosomal X-linked of and both areas hypertrichosis, androgen-dependent generalized dur- the For occurs in hair terminal puberty to ing hair vellus the of conversion whereas pigmented A and long, [4]. medullated often cm and 2 coarser longer, than is latter more seldom terminal and and occasionally pigmented unmedullated, hair soft, being vellus former into the with divided hair, be can hair Postnatal fine, usually is hair, hair unpigmented shed Lanugo usually shafts. and hair unmedullated diam- soft, of structure, pigmentation on and based types eter the hair with as of accordance delineation hair in not current of are reports denomination several the in hair and lanugo description type [4]. extracu- hair inheritance with of of The pattern association nosology the an (3) (2) and precise type, abnormalities taneous a hair the defining (1) are factors CGH crucial three The hypertrichosis 3]. and [2, lanuginosa syndrome universalis Ambras lanuginosa, hypertrichosis chosis hypertri- as congenital lanuginosa, used such hypertrichosis universalis, being confusingly, terms and several classification with interchangeably CGH, the of concerning portraits nomenclature literature and in obscu- the Considerable found in century. prevails be 16th rity the can since cases literature documented More and 2]. well [1, feature less this with or disorders of genetic descriptions nine of least number at the given higher, much probably eateto emtlg,Freiburg Dermatology, of Department Allergy, and Dermatology of Department oct hsatce hnW igJ apeR ogntlgnrlzdhprrcoi emnls rpsdcasfiainadape oaodteabgostr “Ambras term ambiguous the avoid to plea a and classification proposed a terminalis: hypertrichosis generalized Congenital R. Happle J, Ring syndrome”. W, Chen article: this cite To nutero in a enetmtdt eoei ilo u is but billion a in one be to estimated been incidence Its has history. a human is in rarity (CGH) conspicuous hypertrichosis generalized ongenital .Chen W. u Dermatol J Eur ◦ ,MyJn 2015 May-June 3, uigteegt rnnhmnho gestation. of month ninth or eighth the during 1 2 1 05 53:237doi:10.1684/ejd.2015.2529 223-7 25(3): 2015; hsslngns,tria hair terminal lanuginosa, chosis words: future. jettisoned. the Key be in now nor should past term the misleading in this neither Hence, meaning, name specific various the no that to degree has such applied “Ambras” to differ been that hypertrichosis thus congenital has of types syndrome” Xq24-q27.1. and “Ambras 17q24.2-q24.3 designation gene 8q22, include The Potential may lanuginosa. far hypertrichosis so identified of loci example “Ambras an as son. as categorized her “Ambras syndrome” classified been and mistakenly likewise have Pastrana reports has some Julia Moreover, CGHT syndrome”. of of cases type historical X-linked particu- the An a by probably typified is entity hyperplasia syn- gingival lar a with associated probably, dominant CGHT family autosomal trait. an as in This inherited dentition, exhibited abnormal Austria. with children, type Innsbruck, to dromic his near analogized and Gonzales erroneously Castle Petrus was Ambras of which paintings CGHT portrait describe nonsyndromic the to 1993 of in case Baumeister by a coined first was hair. terminal syndrome” of “Ambras growth excessive continuing with heteroge- diseases of a group is nous (CGHT) terminalis hypertrichosis generalized Congenital syndrome” “Ambras term to ambiguous plea the a avoid and classification proposed a terminalis: hypertrichosis generalized Congenital mrssnrm,cneia yetihss hypertri- hypertrichosis, congenital syndrome, Ambras rm” nhmn n h o hntp nmice in phenotype Koa syn- the (“Ambras and hypertrichosis humans [6-8]. to in leading drome”) 1, syndrome downregulate might positional of effect a indicated positional expression study exert long-range subsequent this A to [5]. that shown phenotype pericentric the later on a effect was with which 8q22 Munich, inversion, involving Ring, abnormality Johannes chro- 14 structural mosome a Pr. of identified later age and studies Genetic the Germany). Andres at Christian findings psy- (Dr. laboratory physical, or a remarkable mental without chomotor, 2003, growth hair In orig- Baumeister excessive girl by [5]. Greek described three-year-old canal inally then typically the auditory of region, forehead, external reexamination preauricular the the and on involving cheeks especially nose, hair) eyelids, terminal (which by hair” actually “vellus proposed growing was continually first diffuse, of was onset affected syndrome” the “Ambras Baumeister of name stage The developmental and individuals. account ethnicity into take should the stature”, “short or contour” hypertelorism, “nasal face, “coarse” or abnor- “triangular” of as judgment such the mality, and varies deformity facial other and of or extent degree the dysmorphism However, facial [2]. abnormalities with extracutaneous Syndromic associated disease. be same can the cases within hyper- even of density varies, the trichosis and coverage of extent the The of “sporadic”. spectrum as described been have cases other whereas n19 odfieptet ihcongenital with patients define to 1993 in al. et h eeo trichorhinophalangeal of gene the TRPS1, u emtl21;2() 223-7 25(3): 2015; Dermatol J Eur tal. et hwdpersistent showed 223 Table1. Different types of congenital geneneralized hypertrichosis terminalis (CGHT) with continuously and vigorously growing terminal hair remaining in adulthod.

Examples and references Extracutaneous defects Remarks Nonsyndromic sporadic CGHT Historical cases: Barbara Urselerin No • Potential gene locus: 8q22 (Augsburg, Germany), Stephan [5], 17q24.2-q24.3 [10, 11] Bibrowski (Lionel the Lion-faced • Possibility of heritability Man, Poland) cannot be excluded as most of Media reports: Supatra Sasuphan these patients did not have (Thailand), Prithviraj Patil (India) offspring. Medical reports: Baumeister FA et al. (Greece) [5]; Sun M et al. (China) [10]; Goel N et al. (India) [3]; DeStefano GM et al. (patient from Mexico) [11] Syndromic autosomal Historical cases: The family of Dental anomalies dominant CGHT Ambras (Tenerife, Canary islands?), The hairy Burmese family (Myanmar)

Historical cases: Julia Pastrana Gingival hyperplasia, short • Potential gene locus: (Mexico) stature 17q24.2-q24.3 [10] Medical reports (sporadic cases): • The inheritance in sporadic Ray AK (India) [14]; Winter GB cases remains undetermined. et al. (London, England) [15], Guevara-Sanginés E et al. (Mexico) [16]; Canún S et al. (Mexico) [17], Sun et al. (China, patient KK) [10], DeStefano GM et al. (patient from Yemen) [11] X-linked CGHT, nonsyndromic Medical reports: Macías-Flores No • Males were consistently more MA et al. (Mexico) [18] severely affected than females • Potential gene locus: Xq24-q27.1

X-linked CGHT, syndromic Medical reports: Tadin-Strapps Deafness, dental anomalies • Potential gene locus: M et al. (Mexico) [21] Xq24-q27.1.

Zhu H et al., (China) [23] Scoliosis and spina bifida (in • Potential gene locus: Xq27.1 one case)

(Origin of the patient reported); [references]

The terminology of “Ambras syndrome” as proposed by typically ascribed to this group, because, except for a Baumeister et al. was based on the CGH terminalis (CGHT) somewhat coarse facial contour, the affected individuals had demonstrated in the portraits of Petrus Gonzales and his no extracutaneous anomalies such as dental anomalies, gin- children (the family of Ambras), exhibited in Ambras Cas- gival overgrowth or mental deficiency [10]. Genetic studies tle, located near Innsbruck, Austria [5]. In our view, the showed autosomal dominant inheritance with pathogenic current use of “Ambras syndrome” to describe continu- copy-number mutations on 17q24.2-q24.3. None of these ous vigorous growth of thick terminal hair includes three cases showed extracutaneous defects. Another recent study different major groups of patients with CGHT (table 1): using whole genome sequencing in an unrelated sporadic case from Mexico identified a 1.3 Mb cryptic deletion of 17q24.2-q24.3 encompassing the ATP-binding cassette transporter ABCA5, a cholesterol transporter gene, with dra- Group 1: Nonsyndromic sporadic matic reduction of ABCA5 protein levels throughout the CGHT patient’s hair follicles [11].

This type often occurs sporadically. The case described by Baumeister can be reclassified as belonging to this Group 2: Syndromic autosomal group, based on our follow-up observation. Other possi- ble cases include historical reports on Barbara Urselerin dominant CGHT from Augsburg, Germany, Stephan Bibrowski from Poland (better known as “Lionel the Lion-faced Man”) and some This type is exemplified by “the family of Ambras” with recent case reports [3, 9], as well as media reports (a girl Petrus Gonzales and his three children as well as at least named Supatra Sasuphan from Thailand and a boy named one of their descendants in the third generation [5, 12]. The Prithviraj Patil from India). The three families recently hairy Burmese family in the nineteenth century was another described by Sun et al. from China can also be pheno- example, beginning with Shwe-Maong, his daughter,

224 EJD, vol. 25, n◦ 3, May-June 2015 Table 2. Examples of autosomal dominant diseases showing less dense and extensive CGHT with multiple congenital abnor- malities of greater severity and compromised life expectancy

Main clinical features Hypertrichosis Gene/Locus MIM No. Cantú syndrome (OMIM • Facial dysmorphism Forehead, arms and legs, and 12p12.1/ABCC9/601439 239850) (macrocephaly, broad nasal part of the trunk bridge, epicanthal folds, wide mouth, and full lips) • Neonatal macrosomia • Psychomotor retardation • Osteochondrodysplasia • Cardiomegaly Cornelia de Lange syndrome-1 • Facial dysmorphism Forehead, back and extremities 5p13.2/NIPBL/608667 (OMIM 122470) (microcephaly, arched eyebrows, synophrys, ptosis, anteverted nares, maxillary prognathism, long philtrum, thin lips, and ‘carp’ mouth) • Prenatal and postnatal growth retardation • Psychomotor retardation • Short arms and fingers • Gastroesophageal reflux disease Barber-Say syndrome (OMIM • Facial dysmorphism Back and neck Unknown 209885) (macrostomia, sparce eyebrows, ocular telecanthus, bilateral ectropion, abnormal and low-set ears, bulbous nasal tip with hypoplastic alae nasi, and low frontal hairline) • Nipple hypoplasia or absence • Hyperlaxity and redundancy of skin, • Anomalous external genitalia Schinzel-Giedion syndrome • Facial dysmorphism (midface Generalized but sparing the 18q12.3/ SETBP1/611060 (OMIM 269150) hypoplasia, high protruding face. Can recede during infancy forehead) • Severe mental retardation • Skeletal abnormalities • Genitourinary and renal malformations • Cardiac defects • Neuroepithelial neoplasia Zimmermann-Laband • Gingival fibromatosis, Generalized but sparing the 3p14.3/unknown syndrome (OMIM 135500) abnormalities of the cartilage of face the nose and/or ears • Dysplastic or absent nails • Hypoplasia of the distal phalanges • Scoliosis • Hepatosplenomegaly

Mahphoon, and one of two grandsons, Moung-Phoset, and chomotor development. Another patient from Yemen with great-grand-daughter, Mah-Mé [13]. An X-linked transmis- gingival hyperplasia and epilepsy was born into a consan- sion is highly unlikely because males and females were guineous family, indicating an autosomal recessive trait. A affected to the same degree. These two families have been splice mutation in ABCA5 was found to cause a decrease described as having deficient dentition but they were of in protein levels throughout the patient’s hair follicles normal stature as compared to their ethnicity. The early [11]. designation as “congenital hypertrichosis lanuginosa” was incorrect. CGHT with gingival hyperplasia (gingival fibromatosis) may be considered as a particular subtype of this group. A Group 3: X-linked CGHT typical example is Julia Pastrana (1834-1860) and her son [2]. Sporadic cases have been described in several reports A nonsyndromic X-linked type, originally described by [10, 14-17]. All these patients were of rather short stature, Macias-Flores et al. in a Mexican five-generation family but had a normal number of teeth and unremarkable psy- with 19 affected individuals, is characterized by excessive

EJD, vol. 25, n◦ 3, May-June 2015 225 Table 3. Examples of autosomal recessive diseases with very early onset of severe insulin resistance showing acanthosis nigricans and mild to moderate generalized hirsutism

Main clinical features Skin manifestations Gene/Locus MIM No. Rabson-Mendenhall syndrome Growth retardation Acanthosis nigricans 19p13.2/INSR(compound (OMIM 262190) Pineal hypertrophy Hirsutism heterozygosity)/147670 Dental abnormalies Phallic enlargement/precocious puberty Insulin resistant diabetes mellitus Early death (5-15 years) Donohue syndrome (OMIM Elfin faces Acanthosis nigricans 19p13.2/ 246200) Growth retardation Hirsutism INSR(homozygosity)/147670 Gingival hyperplasia Phallic enlargement/precocious puberty Lipodystrophy Insulin resistant diabetes mellitus Death in early infancy Berardinelli-Seip syndrome Congenital generalized lipodystrophy Acanthosis nigricans 11q12.3/ BSCL2/606158 (OMIM 269700) Extreme insulin Hirsutism resistance/hypertriglyceridemia Hepatosplenomegaly/hepatic steatosis Hypertrophic cardiomyopathy

hair growth present at birth, which increases during the In conclusion, “Ambras syndrome” appears to be a use- first year of life, sparing the palms, soles and mucosae less term because it deludes one into believing that a [18]. There was no gingival hypertrophy or any other sys- nosologically uniform entity with this name may exist. In temic abnormality. Males were consistently more severely fact, this designation never had a specific meaning. It was affected than females, with the latter showing a patchy or interchangeably applied to various types of hypertrichosis checkerboard pattern of excessive hair distribution, reflect- that differ from each other both clinically and genetically. ing functional X-chromosome mosaicism. The gene locus Hence, the name “Ambras syndrome” should no longer be was mapped to Xq24-q27.1 [19, 20]. used to delineate any of the different types of congenital Moreover, syndromic X-linked forms have also been hypertrichosis.  described. Tadin-Strapps et al. observed a large Mexican kindred characterized by a combination of CGHT, deaf- Disclosure. Financial support: none. Conflict of interest: ness and abnormal shape and position of teeth, inherited as none. an X-linked trait [21]. Males were more severely affected than females, who exhibited only mild hypertrichosis with- out deafness or dental anomalies. Haplotype analysis in this pedigree revealed linkage to a 13-cM region on Xq24- q27.1. A position effect on fibroblast growth factor 13 was recently found to be associated with this phenotype [22]. In another study of a five-generation Chinese family by Zhu References et al, interchromosomal insertions at the same Xq27.1 site mediated by a human specific palindrome near SOX3 was identified [23]. From 11 affected individuals, all of the four 1. Garcia-Cruz D, Figuera LE, Cantu JM. Inherited hypertrichoses. Clin examined males had severe hypertrichosis associated with Genet 2002; 61: 321-9. scoliosis (plus spina bifida in one case only), whereas all 2. Bondeson J, Miles AE. Julia Pastrana, the nondescript: an exam- affected females had only mild hypertrichosis. ple of congenital, generalized hypertrichosis terminalis with gingival Another group of patients with less dense and exten- hyperplasia. Am J Med Genet 1993; 47: 198-212. sive CGHT show mostly multiple congenital abnormalities 3. Goel N, Rajaram S, Gupta B, Gupta K. Familial congenital general- of greater severity and compromised life expectancy ized hypertrichosis. Indian J Dermatol Venereol Leprol 2013; 79: 849. [1, 24-30]. These may include autosomal dominant dis- 4. de Berker DAR, Messenger AG, Sinclair RD. Disorders of hair. In: Burns T, Breathnach S, Cox N, Griffiths C, eds. Rook’s Text- eases, such as Cantú syndrome, Cornelia de Lange book of Dermatology. 7th edn. Massachusetts: Blackwell, 2004: 63, syndrome, Barber-Say syndrome, Schinzel-Giedion syn- 91-3. drome and Zimmermann-Laband syndrome (table 2), and 5. Baumeister FA, Egger J, Schildhauer MT, Stengel-Rutkowski S. autosomal recessive diseases with a very early onset of Ambras syndrome: delineation of a unique hypertrichosis universalis severe insulin resistance and acanthosis nigricans, such congenita and association with a balanced pericentric inversion (8) as Rabson-Mendenhall syndrome, Donohue syndrome and (p11.2; q22). Clin Genet 1993; 44: 121-8. Berardinelli-Seip syndrome (table 3). By contrast, most of 6. Fantauzzo KA, Tadin-Strapps M, You Y, et al. A position effect on TRPS1 is associated with Ambras syndrome in humans and the Koala the patients in our analysis tended to maintain continuously phenotype in mice. Hum Mol Genet 2008; 17: 3539-51. and strongly growing terminal hair in adulthood, indicat- 7. Tadin M, Braverman E, Cianfarani S, et al. Complex cytogenetic ing a peculiar category of hypertrichosis, probably with a rearrangement of chromosome 8q in a case of Ambras syndrome.Am different pathogenesis (table 1). J Med Genet 2001; 102: 100-4.

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