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Rapp-Hodgkin ectodermal dysplasia syndrome(RHS)

MedGen UID:
315656
Concept ID:
C1785148
Disease or Syndrome
Synonyms: Ectodermal dysplasia, anhidrotic, with cleft lip/palate; Isolated Cleft Lip/Cleft Palate (Orofacial Cleft 8); Rapp-Hodgkin syndrome; RHS
SNOMED CT: Rapp-Hodgkin ectodermal dysplasia syndrome (7731005); Rapp-Hodgkin type of ectodermal dysplasia (7731005)
 
Gene (location): TP63 (3q28)
 
Monarch Initiative: MONDO:0007508
OMIM®: 129400
Orphanet: ORPHA3022

Disease characteristics

Excerpted from the GeneReview: TP63-Related Disorders
The TP63-related disorders comprise six overlapping phenotypes: Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (which includes Rapp-Hodgkin syndrome). Acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome. Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3). Limb-mammary syndrome. Split-hand/foot malformation type 4 (SHFM4). Isolated cleft lip/cleft palate (orofacial cleft 8). Individuals typically have varying combinations of ectodermal dysplasia (hypohidrosis, nail dysplasia, sparse hair, tooth abnormalities), cleft lip/palate, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypopigmentation, hypoplastic breasts and/or nipples, and hypospadias. Findings associated with a single phenotype include ankyloblepharon filiforme adnatum (tissue strands that completely or partially fuse the upper and lower eyelids), skin erosions especially on the scalp associated with areas of scarring, and alopecia, trismus, and excessive freckling. [from GeneReviews]
Authors:
V Reid Sutton  |  Hans van Bokhoven   view full author information

Additional descriptions

From OMIM
Rapp-Hodgkin syndrome (RHS) is characterized by anhidrotic ectodermal dysplasia and cleft lip/palate. Patients have characteristic facies (narrow nose and small mouth), wiry, slow growing, and uncombable hair, sparse eyelashes and eyebrows, obstructed lacrimal puncta/epiphora, bilateral stenosis of external auditory canals, microsomia, hypodontia, cone-shaped incisors, enamel hypoplasia, and dystrophic nails (summary by Kantaputra et al., 2003).  http://www.omim.org/entry/129400
From MedlinePlus Genetics
Additional features of AEC syndrome can include limb abnormalities, most commonly fused fingers and toes (syndactyly). Less often, affected individuals have permanently bent fingers and toes (camptodactyly) or a deep split in the hands or feet with missing fingers or toes and fusion of the remaining digits (ectrodactyly). Hearing loss is common, occurring in more than 90 percent of children with AEC syndrome. Some affected individuals have distinctive facial features, such as small jaws that cannot open fully and a narrow space between the upper lip and nose (philtrum). Other signs and symptoms can include the opening of the urethra on the underside of the penis (hypospadias) in affected males, digestive problems, absent tear duct openings in the eyes, and chronic sinus or ear infections.

A condition known as Rapp-Hodgkin syndrome has signs and symptoms that overlap considerably with those of AEC syndrome. These two syndromes were classified as separate disorders until it was discovered that they both result from mutations in the same part of the same gene. Most researchers now consider Rapp-Hodgkin syndrome and AEC syndrome to be part of the same disease spectrum.

Many infants with AEC syndrome are born with an eyelid condition known as ankyloblepharon filiforme adnatum, in which strands of tissue partially or completely fuse the upper and lower eyelids. Most people with AEC syndrome are also born with an opening in the roof of the mouth (a cleft palate), a split in the lip (a cleft lip), or both. Cleft lip or cleft palate can make it difficult for affected infants to suck, so these infants often have trouble feeding and do not grow and gain weight at the expected rate (failure to thrive).

Among the most common features of AEC syndrome are missing patches of skin (erosion). In affected infants, skin erosion most commonly occurs on the scalp. It tends to recur throughout childhood and into adulthood, frequently affecting the scalp, neck, hands, and feet. Skin erosion ranges from mild to severe and can lead to life-threatening infection in infancy, scarring, and hair loss. Other ectodermal abnormalities in AEC syndrome include changes in skin coloring; brittle, sparse, or missing hair; misshapen or absent fingernails and toenails; and malformed or missing teeth. Affected individuals may also have an inability to control their body temperature because of missing or nonfunctioning sweat glands causing overheating or hypothermia.

Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is a form of ectodermal dysplasia, a group of about 180 conditions characterized by abnormal development of ectodermal tissues including the skin, hair, nails, teeth, eyes, ears, and sweat glands.  https://medlineplus.gov/genetics/condition/ankyloblepharon-ectodermal-defects-cleft-lip-palate-syndrome

Clinical features

From HPO
Hypoplastic labia majora
MedGen UID:
107566
Concept ID:
C0566899
Finding
Undergrowth of the outer labia.
Hypospadias
MedGen UID:
163083
Concept ID:
C0848558
Congenital Abnormality
Abnormal position of urethral meatus on the ventral penile shaft (underside) characterized by displacement of the urethral meatus from the tip of the glans penis to the ventral surface of the penis, scrotum, or perineum.
Syndactyly
MedGen UID:
52619
Concept ID:
C0039075
Congenital Abnormality
Webbing or fusion of the fingers or toes, involving soft parts only or including bone structure. Bony fusions are referred to as "bony" syndactyly if the fusion occurs in a radio-ulnar axis. Fusions of bones of the fingers or toes in a proximo-distal axis are referred to as "symphalangism".
2-3 toe cutaneous syndactyly
MedGen UID:
98470
Concept ID:
C0432040
Congenital Abnormality
Palmoplantar keratoderma
MedGen UID:
1635750
Concept ID:
C4551675
Disease or Syndrome
Abnormal thickening of the skin of the palms of the hands and the soles of the feet.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Stenosis of the external auditory canal
MedGen UID:
140758
Concept ID:
C0395837
Finding
An abnormal narrowing of the external auditory canal.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Hypoplasia of the maxilla
MedGen UID:
66804
Concept ID:
C0240310
Congenital Abnormality
Abnormally small dimension of the Maxilla. Usually creating a malocclusion or malalignment between the upper and lower teeth or resulting in a deficient amount of projection of the base of the nose and lower midface region.
Recurrent otitis media
MedGen UID:
155436
Concept ID:
C0747085
Disease or Syndrome
Increased susceptibility to otitis media, as manifested by recurrent episodes of otitis media.
Cleft upper lip
MedGen UID:
40327
Concept ID:
C0008924
Congenital Abnormality
A gap or groove in the upper lip. This is a congenital defect resulting from nonfusion of tissues of the lip during embryonal development.
Carious teeth
MedGen UID:
8288
Concept ID:
C0011334
Disease or Syndrome
Caries is a multifactorial bacterial infection affecting the structure of the tooth. This term has been used to describe the presence of more than expected dental caries.
Enamel hypoplasia
MedGen UID:
3730
Concept ID:
C0011351
Disease or Syndrome
Developmental hypoplasia of the dental enamel.
Partial congenital absence of teeth
MedGen UID:
43794
Concept ID:
C0020608
Congenital Abnormality
Tooth agenesis in some form is a common human anomaly that affects approximately 20% of the population. Although tooth agenesis is associated with numerous syndromes, several case reports describe nonsyndromic forms that are either sporadic or familial in nature, as reviewed by Gorlin et al. (1990). The incidence of familial tooth agenesis varies with each class of teeth. Most commonly affected are third molars (wisdom teeth), followed by either upper lateral incisors or lower second premolars; agenesis involving first and second molars is very rare. Also see 114600 and 302400. Selective tooth agenesis without associated systemic disorders has sometimes been divided into 2 types: oligodontia, defined as agenesis of 6 or more permanent teeth, and hypodontia, defined as agenesis of less than 6 teeth. The number in both cases does not include absence of third molars (wisdom teeth). Faulty use of the terms, however, have confounded their use. The term 'partial anodontia' is obsolete (Salinas, 1978). Genetic Heterogeneity of Selective Tooth Agenesis Other forms of selective tooth agenesis include STHAG2 (602639), mapped to chromosome 16q12; STHAG3 (604625), caused by mutation in the PAX9 gene (167416) on chromosome 14q12; STHAG4 (150400), caused by mutation in the WNT10A gene (606268) on chromosome 2q35; STHAG5 (610926), mapped to chromosome 10q11; STHAG7 (616724), caused by mutation in the LRP6 gene (603507) on chromosome 12p13; STHAG8 (617073), caused by mutation in the WNT10B gene (601906) on chromosome 12q13; STHAG9 (617275), caused by mutation in the GREM2 gene (608832) on chromosome 1q43; STHAG10 (620173), caused by mutation in the TSPEAR gene (612920) on chromosome 21q22; and STHAGX1 (313500), caused by mutation in the EDA gene (300451) on chromosome Xq13. A type of selective tooth agenesis that was formerly designated STHAG6 has been incorporated into the dental anomalies and short stature syndrome (DASS; 601216). Of 34 unrelated patients with nonsyndromic tooth agenesis, van den Boogaard et al. (2012) found that 56% (19 patients) had mutations in the WNT10A gene (STHAG4), whereas only 3% and 9% had mutations in the MSX1 (STHAG1) and PAX9 (STHAG3) genes, respectively. The authors concluded that WNT10A is a major gene in the etiology of isolated hypodontia. Genotype-Phenotype Correlations Yu et al. (2016) observed that the most frequently missing permanent teeth in WNT10B-associated oligodontia were the lateral incisors (83.3%), whereas premolars were missing only 51.4% of the time, which they noted was a pattern 'clearly different' from the oligodontia patterns resulting from WNT10A mutations. They also stated that the selective pattern in WNT10B mutants was different from that associated with mutations in other genes, such as MSX1, in which second premolars are missing, and PAX9, in which there is agenesis of molars.
Narrow mouth
MedGen UID:
44435
Concept ID:
C0026034
Congenital Abnormality
Distance between the commissures of the mouth more than 2 SD below the mean. Alternatively, an apparently decreased width of the oral aperture (subjective).
Velopharyngeal insufficiency
MedGen UID:
52992
Concept ID:
C0042454
Finding
Inability of velopharyngeal sphincter to sufficiently separate the nasal cavity from the oral cavity during speech.
High forehead
MedGen UID:
65991
Concept ID:
C0239676
Finding
An abnormally increased height of the forehead.
Microdontia
MedGen UID:
66008
Concept ID:
C0240340
Congenital Abnormality
Decreased size of the teeth, which can be defined as a mesiodistal tooth diameter (width) more than 2 SD below mean. Alternatively, an apparently decreased maximum width of tooth.
Conical tooth
MedGen UID:
82730
Concept ID:
C0266037
Congenital Abnormality
An abnormal conical form of the teeth, that is, a tooth whose sides converge or taper together incisally.
Taurodontism
MedGen UID:
75596
Concept ID:
C0266039
Disease or Syndrome
Increased volume of dental pulp of permanent molar characterized by a crown body-root ratio equal or larger than 1:1 or an elongated pulp chambers and apical displacement of the bifurcation or trifurcation of the roots.
Narrow nose
MedGen UID:
98086
Concept ID:
C0426422
Finding
Interalar distance more than 2 SD below the mean for age, or alternatively, an apparently decreased width of the nasal base and alae.
Sparse eyebrow
MedGen UID:
371332
Concept ID:
C1832446
Finding
Decreased density/number of eyebrow hairs.
Underdeveloped nasal alae
MedGen UID:
322332
Concept ID:
C1834055
Congenital Abnormality
Thinned, deficient, or excessively arched ala nasi.
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Small, conical teeth
MedGen UID:
342115
Concept ID:
C1851883
Finding
Absent lacrimal punctum
MedGen UID:
356683
Concept ID:
C1867060
Disease or Syndrome
No identifiable superior and/or inferior lacrimal punctum.
Cleft palate
MedGen UID:
756015
Concept ID:
C2981150
Congenital Abnormality
Cleft palate is a developmental defect of the palate resulting from a failure of fusion of the palatine processes and manifesting as a separation of the roof of the mouth (soft and hard palate).
Bifid uvula
MedGen UID:
1646931
Concept ID:
C4551488
Congenital Abnormality
Uvula separated into two parts most easily seen at the tip.
Hypohidrosis
MedGen UID:
43796
Concept ID:
C0020620
Disease or Syndrome
Abnormally diminished capacity to sweat.
Dry skin
MedGen UID:
56250
Concept ID:
C0151908
Sign or Symptom
Skin characterized by the lack of natural or normal moisture.
Nail dystrophy
MedGen UID:
66368
Concept ID:
C0221260
Disease or Syndrome
Onychodystrophy (nail dystrophy) refers to nail changes apart from changes of the color (nail dyschromia) and involves partial or complete disruption of the various keratinous layers of the nail plate.
Small nail
MedGen UID:
537942
Concept ID:
C0263523
Finding
A nail that is diminished in length and width, i.e., underdeveloped nail.
Onychogryposis
MedGen UID:
82671
Concept ID:
C0263537
Disease or Syndrome
Nail that appears thick when viewed on end.
Thin skin
MedGen UID:
140848
Concept ID:
C0423757
Finding
Reduction in thickness of the skin, generally associated with a loss of suppleness and elasticity of the skin.
Fine hair
MedGen UID:
98401
Concept ID:
C0423867
Finding
Hair that is fine or thin to the touch.
Anhidrotic ectodermal dysplasia
MedGen UID:
310309
Concept ID:
C1706004
Congenital Abnormality
Slow-growing hair
MedGen UID:
371309
Concept ID:
C1832348
Finding
Hair whose growth is slower than normal.
Sparse eyelashes
MedGen UID:
375151
Concept ID:
C1843300
Finding
Decreased density/number of eyelashes.
Progressive alopecia
MedGen UID:
342116
Concept ID:
C1851885
Finding
Progressive loss of hair.
Uncombable hair
MedGen UID:
348660
Concept ID:
C1860607
Finding
Hair that is disorderly, stands out from the scalp, and cannot be combed flat.
Pili canaliculi
MedGen UID:
348148
Concept ID:
C1860608
Finding
A characteristic triangular, kidney- or heat-shaped diameter of hair shafts with typical longitudinal canalicular deformation as observable by scanning electron microscopy.
Decreased number of sweat glands
MedGen UID:
867216
Concept ID:
C4021574
Finding
The presence of fewer than normal sweat glands.
Sparse hair
MedGen UID:
1790211
Concept ID:
C5551005
Finding
Reduced density of hairs.
Supernumerary nipple
MedGen UID:
120564
Concept ID:
C0266011
Congenital Abnormality
Presence of more than two nipples.
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).

Professional guidelines

PubMed

Karthikeyani S, Thirumurthy VR, Yuvaraja BA
J Indian Soc Pedod Prev Dent 2016 Apr-Jun;34(2):192-5. doi: 10.4103/0970-4388.180453. PMID: 27080974

Recent clinical studies

Prognosis

Kannu P, Savarirayan R, Ozoemena L, White SM, McGrath JA
Am J Med Genet A 2006 Apr 15;140(8):887-91. doi: 10.1002/ajmg.a.31187. PMID: 16532463
Shotelersuk V, Janklat S, Siriwan P, Tongkobpetch S
Clin Exp Dermatol 2005 May;30(3):282-5. doi: 10.1111/j.1365-2230.2005.01722.x. PMID: 15807690
Chan I, McGrath JA, Kivirikko S
Clin Exp Dermatol 2005 Mar;30(2):183-6. doi: 10.1111/j.1365-2230.2004.01715.x. PMID: 15725251

Clinical prediction guides

Kannu P, Savarirayan R, Ozoemena L, White SM, McGrath JA
Am J Med Genet A 2006 Apr 15;140(8):887-91. doi: 10.1002/ajmg.a.31187. PMID: 16532463
Shotelersuk V, Janklat S, Siriwan P, Tongkobpetch S
Clin Exp Dermatol 2005 May;30(3):282-5. doi: 10.1111/j.1365-2230.2005.01722.x. PMID: 15807690
Chan I, McGrath JA, Kivirikko S
Clin Exp Dermatol 2005 Mar;30(2):183-6. doi: 10.1111/j.1365-2230.2004.01715.x. PMID: 15725251
Stasiowska B, Sartoris S, Goitre M, Benso L
Arch Dis Child 1981 Oct;56(10):793-5. doi: 10.1136/adc.56.10.793. PMID: 7305420Free PMC Article

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